bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with advanced solid tumors.
Authors: Chi Zhihong , Tang Bixia , Sheng Xinan , Si Lu , Cui Chuanliang , Kong Yan , Li Dan , Li Si Ming , Yan Xieqiao , Mao Li Li , Lian Bin , Bai Xue , Wang Xuan , Zhou Li , Yu Jiayi , Xu Mingli , Dong Lihou , Song Haifeng , Guo Jun ,   Shanghai Junshi Biosciences
Published: September 2018

3067 Background: JS001 blocks the interaction between PD-1 and its ligands and eradicates established tumor in human PD-1 Knock-in mouse model. Methods: A Phase I open-label study is designed to evaluate the safety and tolerability of JS001 in advanced solid tumor pts who are refractory to standard therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg followed by a dose expansion. (Clinical Trial ID: NCT02836795). Results: As of January 27, 2017, pts enrollment has been completed with 36 pts from 3 indications (22 Melanoma; 9 Urothelial Carcinoma; 5 Renal Cell Carcinoma). The majority of melanomas are acral and mucosal origin. No DLT was observed and no MTD was reached in the study. The most common treatment-related AEs were grade 1/2, including hyper- or hypo-thyroidism (42%), rash (39%), fever (28%), leukopenia (22%), elevation of liver enzymes (19%), anorexia (17%), and fatigue (14%). Treatment–related grade 3 AEs include proteinuria (n = 1), and lipase increase (n = 2). The emergence of AEs is not dose related. JS001 PK shows dose-dependent exposure with the elimination half-life of 6 to 12 days. Among 32 evaluable pts, 1 pt have complete response (melanoma), 6 pts have partial response (3 melanoma, 2 RCC and 1 UC), and 10 pts achieve stable disease, for an ORR of 22% and a DCR of 53%. 6 out of 7 CR/PR pts still have ongoing response. Two groups of pts benefited most from JS001 treatment, pts with high tumor-infiltrating lymphocytes (TIL) (50% ORR) and pts with > 1% PD-L1 expression in tumor biopsy (46% ORR). Conclusions: JS001 exhibited a favorable safety profile in human. Treatment related AEs are in line with those from approved drugs in the same class. JS001 has demonstrated promising anti-tumor activity, especially in previously under-evaluated acral (20% ORR, 53% DCR) and mucosal (25% ORR, 50% DCR) melanomas. Clinical trial information: NCT02836795.
Validation of the Princess Margaret immune oncology prognostic index (PM-IPI) for patients (pts) treated in immune oncology (IO) early phase trials.
Authors: Day Daphne , Spreafico Anna , Lheureux Stephanie , Abdul Razak Albiruni Ryan , Hansen Aaron Richard , Wang Lisa , Butler Marcus O. , Siu Lillian L. , Bedard Philippe L. 
Published: September 2018

3070 Background: We previously developed the PM-IPI (ECOG performance status [PS] > / = 1, albumin < lower limit of normal [LLN] and > 2 metastatic sites) from a retrospective cohort of 192 pts treated in phase I IO trials (development cohort). The PM-IPI prognosticated for overall survival (OS), 90-day mortality (90DM) and was associated with improved overall response rate (ORR) and progression free survival (PFS). Our aim was to prospectively validate the PM-IPI in an independent cohort of pts treated on IO trials. Methods: We included 152 consecutively treated advanced solid tumor pts at PM from Aug 2015 to Aug 2016 in 24 IO early phase trials, targeting immune checkpoints and/or co-stimulatory molecules. Pts from the development cohort were excluded. The ability of the PM-IPI to prognosticate OS and 90DM, and predict PFS and ORR was compared with the previously published Royal Marsden Hospital prognostic score (RMI: albumin < 35g/L, LDH > upper limit of normal and > 2 metastatic sites) using the C-index (0.5 = no discrimination, 1 = perfect discrimination) and Area Under the Curve (AUC). Results: Median age was 59y (range 20-86), 28%/72% of pts were ECOG PS 0/1, and 88% had at least 1 prior systemic therapy (range 0-7). The most common tumor sites were gastrointestinal (23%), gynecological (16%), head and neck (15%) and urological (10%). Median PFS and OS were 9.0 and 39.7 wk respectively and 90DM was 14%. ORR was 7% by RECIST 1.1, immune related RECIST or immune related response criteria. In multivariable analysis, ECOG PS > / = 1 (HR 2.7, p = 0.01), albumin < LLN (HR 2.1, p = 0.01) and > 2 metastatic sites (HR 1.8, p = 0.04) were independently prognostic for OS. Pts with a PM-IPI score of 2-3 compared to 0-1 had significantly shorter OS (HR 3.3, p < 0.0001), PFS (HR 1.7, p = 0.005) and higher 90DM (OR 12.2, p = 0.019), and a trend towards lower ORR (OR 0.4, p = 0.15). The prognostic performance of PM-IPI was superior to the RMI for OS and 90DM, but not PFS and ORR (Table). Conclusions: In this independent validation cohort, the PM-IPI prognosticated for OS and 90DM and was associated with PFS. Validation in a large external cohort is ongoing. [Table: see text]
Subgroup efficacy evaluation of the AE37 HER2 vaccine in breast cancer patients in the adjuvant setting.
Authors: Peace Kaitlin M. , Mittendorf Elizabeth Ann , Perez Sonia A. , Tzonis Panagiotis , Pistamaltzian Nikolaos Fragkiskos , Anastasopoulou Eleftheria A , Vreeland Timothy J. , Hale Diane F , Clifton Guy T , Litton Jennifer Keating , von Hofe Eric , Ardavanis Alexandros , Papamichail Michael , Peoples George Earl 
Published: September 2018

3088 Background: AE37 is a Ii-Key hybrid of the HER2 peptide AE36 (HER2776-790), which stimulates peptide-specific T cells. We have completed the active phase of a prospective, randomized, multi-center, phase II trial of the AE37 vaccine in the adjuvant setting. The primary analysis, performed after a median follow up (f/u) of 25 months (mo), did not show a significant difference in disease free survival (DFS) between vaccinated and control patients (pts). However, demonstrating the efficacy of cancer vaccines may require more time than other therapies, especially in malignancies with relatively late recurrences like breast cancer. Here, we present updated efficacy data after extended f/u in subgroups of pts stratified by clinicopathologic characteristics. Methods: Clinically disease-free, node positive or high-risk node negative pts with any level of HER2 expression were randomized to receive AE37 + GM-CSF (VG) or GM-CSF alone (CG) following standard of care therapy. Pts received 6 monthly intradermal inoculations during the primary vaccine series (PVS) followed by 4 boosters administered every 6 mo. Kaplan Meier and log rank analyses were performed from the time of the first inoculation in pts who completed at least the PVS, according to stage, node status, tumor size, HER2 expression and ER/PR status. Results: There were no clinicopathologic differences between groups in the 298 enrolled pts (VG = 153, CG = 145). The vaccine is safe and well tolerated. After a median f/u of 55 mo, there was a trend toward improved DFS in the VG among stage IIB/III pts (VG, n = 73, DFS 82% vs CG, n = 61, 67%, HR = 0.48, p = 0.06) and those with low HER2 expression (HER2 LE, VG, n = 68, 89% vs CG, n = 66, 51%, HR = 0.47, p = 0.1). Improved DFS in the VG was documented in patients with both stage IIB/III disease and HER2 LE (VG, n = 39, 90% vs CG, n = 38, 32%, HR 0.3, p = 0.02) and triple negative (TNBC) pts (VG, n = 21, 89% vs CG, n = 21, 0%, HR 0.26, p = 0.05). Conclusions: The AE37 vaccine is safe and well tolerated and has statistically significant efficacy in stage IIB/III pts with HER2 LE and in TNBC pts. This justifies further evaluation in a phase III study enrolling stage IIb/III pts not eligible for trastuzumab treatment and the very high risk TNBC group. Clinical trial information: NCT00524277.
Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: The French participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.
Authors: Andre Thierry , Bonnetain Franck , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Dauba Jérôme , Vernerey Dewi , Aissat Nasredine , Louvet Christophe , Lepère Céline , Dupuis Olivier Jean Marie , Becouarn Yves , Mabro May , Egreteau Joëlle , Bouche Olivier , Deplanque Gael , Ychou Marc , De Gramont Aimery , Taieb Julien ,   GERCOR, FFCD, and UNICANCER (PRODIGE) Study Groups
Published: September 2018

3500 Background: The IDEA international collaboration was established to combine data from 6 randomized trials to assess whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) for 3-year disease free survival (DFS) in stage III colon cancer (CC). Methods: French IDEA randomized patients (pts) between 3M and 6M of CT with mFOLFOX6 or XELOX (physician/pts choice). DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: Among 2022 randomized pts between May 2009 and May 2014, 2010 (99.4%) received CT and were enrolled in the mITT population: 49.9 and 50.1% in 3M and 6M, respectively. 99.5% of the mITT pts had stage III (N1: 74.9%; N2: 25.2%); median age 63.9 years; mFOLFOX6: 90% and XELOX 10% of pts. DFS median follow-up is 50.2 months. There were 578 DFS events (314 in 3M and 264 in 6M arm) leading to a 3-year DFS rate of 72.1% in the 3M vs. 75.7% in the 6M (HR=1.24; 95%CI 1.05–1.46, p=0.0112). For pts receiving mFOLFOX6, 3-year DFS rate was 72.0% in the 3M vs. 76.3% in the 6M (HR=1.27; 95%CI 1.07–1.51 p=0.0069). 94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Median oxaliplatin doses intensity were 96.9% in 3M and 72.1% in 6M (495.0 and 735.1 mg/m2). By considering the neuropathy grade with 15375 neuropathy longitudinal measurements the overall maximal neuropathy grade 0-1/2/3-4 was 63.6/28.5/7.9% in 3M and 33.4/41.3/25.3% in 6M; p<0.0001. At last follow-up assessment, with a median of 43.1 months, final residual grade 2/3-4 neuropathy was 2.1/0.4% in 3M and 5.4/1.3% in 6M; p<0.0001. Conclusions: The IDEA France study, with 90% of patients treated with mFOLFOX6 regimen has shown that 6 months adjuvant treatment is superior to 3 months treatment. IDEA France study results should be considered in line with the international IDEA project that will also be presented at ASCO 2017. Clinical trial information: 2009-010384-16.
Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance).
Authors: Venook Alan P. , Ou Fang-Shu , Lenz Heinz-Josef , Kabbarah Omar , Qu Xueping , Niedzwiecki Donna , Zemla Tyler , Goldberg Richard M. , Hochster Howard S. , O'Neil Bert H. , Sanoff Hanna Kelly , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Innocenti Federico 
Published: September 2018

3503 Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]
Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer.
Authors: Sharma Ricky A. , Wasan Harpreet Singh , Van Hazel Guy A. , Heinemann Volker , Sharma Navesh K. , Taieb Julien , Ricke Jens , Mills Jamie , Tait Nicholas Paul , Boardman Philip , Peeters Marc , Findlay Michael P. N. , Virdee Pradeep Singh , Moschandreas Joanna , Gebski Val , Love Sharon , Gray Alastair , Gibbs Peter 
Published: September 2018

3507 Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS). Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data. Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate ( p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p< 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p< 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months. Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS. Clinical trial information: 83867919.
A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO).
Authors: Li Jin , Qin Shukui , Bai Yuxian , Deng Yanhong , Yang Lei , Xu Rui-hua , Chen Zhendong , Zhong Haijun , Pan Hongming , Shu Yongqian , Yuan Ying , Xu Nong , Zhou Jianfeng , Liu Tianshu , MA DONG , Wu Changping , Cheng Ying , Fan Songhua , Hua Ye , Su Weiguo ,   ASCO Authors' Group
Published: September 2018

3508 Background: Treatment options for third-line metastatic colorectal cancer (mCRC) patients remain limited in China. Fruquintinib, an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, in a phase II study was found to significantly improve progression free survival (“PFS”) in patients with mCRC as compared to placebo (ESMO abs#2111). Based on these results, a Phase III registration trial, FRESCO, was carried out to confirm fruquintinib’s efficacy and safety in third-line mCRC patients (clinicaltrials.gov # NCT02314819). Methods: This is a randomized, double-blind, placebo-controlled, multi-center phase III trial. Patients with mCRC who have failed at least 2 lines of systemic chemotherapy were enrolled from 28 centers in China. Patients were stratified based on prior anti-VEGF therapy and K-ras status and randomized to a fruquintinib or placebo arm in a 2:1 ratio. The primary endpoint was overall survival (“OS”) which was analyzed in the intent-to-treat population. Results: Between December 12, 2014 and May 13, 2016, 416 patients were randomized. Protocol predefined number of OS events for final analysis was reached on January 17, 2017. Fruquintinib significantly improved OS comparing to placebo with a hazard ratio of 0.65 (95% CI: 0.51-0.83; two sided p<0.001). Median OS was 9.30 months [95% CI 8.18-10.45] in the fruquintinib group versus 6.57 months [95% CI 5.88-8.11] in the placebo group. Statistically significant benefits were also seen with fruquintinib in all secondary endpoints, such as PFS, objective response rate and disease control rate. The most frequent fruquintinib-related ≥ Grade 3 treatment emerged adverse events included hypertension (21.6%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (3.2%). Conclusion: In this phase III confirmatory trial, fruquintinib demonstrated a statistically significant and clinically meaningful OS benefit as compared with placebo in mCRC patients in China. Fruquintinib was well tolerated with a safety profile that is consistent with what was reported previously. Clinical trial information: NCT02314819.
Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status.
Authors: Taieb Julien , Kourie Hampig Raphael , Emile Jean-François , Le Malicot Karine , Balogoun Ralyath , Tabernero Josep , Mini Enrico , Folprecht Gunnar , Van Laethem Jean-Luc , Mulot Claire , Bouche Olivier , Aparicio Thomas , Michel Pierre , Thaler Josef , Bridgewater John A. , Van Cutsem Eric , Perkins Géraldine , Salazar Ramon , Lepage Come , Laurent-Puig Pierre 
Published: September 2018

3515 Background: Recent data suggest that the anatomic site of colon primary tumor may be an important factor in the interpretation of molecular markers with clinical outcome in metastatic colon cancer (CC) patients (pts). We assessed here the prognostic value of primary location in fully resected stage III CC pts and its relationship to MSI, RAS and BRAF mutational status. Methods: Pts enrolled in the PETACC-8 trial were analyzed. We categorized tumor site as located proximal (left-sided) or distal (right-sided) to the splenic flexure. The association between tumor location and disease free survival (DFS), survival after relapse (SAR) and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, MSI, BRAF and RASmutation status. The outcome of pts receiving FOLFOX or FOLFOX and cetuximab in the adjuvant setting were also determined according to tumor site. Results: Among the 1869 pts with full molecular data available, 755 (40%) had a right-sided tumor, 164 (10%) were MSI, 942 (50%) were mutated for RAS and 212 (11%) were mutated for BRAF. Right-sided tumor was not prognostic for DFS in the whole population but was associated to a shorter SAR (HR: 1.54 [1.23 - 1.93], p = 0.001) and OS (HR: 1.25 [1.02 - 1.54], p = 0.03). Same results were observed for MSS and for MSI pts. However, when looking at pts mutated for RAS or BRAF(MUT) and those double wild type (DWT) for those mutations, we found that right-sided tumors, when compared to left-sided tumors, was associated with a worst DFS in DWT patients (HR:1.39[1.01-1.92], p = 0.04) and a better DFS in MUT patients (HR:0.77[0.63-0.95], p = 0.01). These results were found independently of the treatment received and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions: In the whole study population of stage III CC pts, though right-sided tumor location influences OS as previously reported, it does not seem to influence DFS but only SAR, when disease becomes metastatic. Interestingly, sidedness seems to influence DFS when splitting the population in MUT or DWT for RAS and BRAF, with a worst DFS for right-sided tumors in DWT and a worst DFS for left-sided tumors in RAS or BRAF mutants. Clinical trial information: 2005-003463-23.
Primary tumor location and efficacy of second-line therapy after initial treatment with FOLFIRI in combination with cetuximab or bevacizumab in patients with metastatic colorectal cancer- FIRE-3 (AIOKRK0306).
Authors: Modest Dominik Paul , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Giessen-Jung Clemens , Jung Andreas , Kirchner Thomas , Heinemann Volker 
Published: September 2018

3525 Background: FIRE3 compared 1st-line therapy with FOLFIRI plus either cetuximab (arm A) or bevacizumab (arm B) in 592 patients (pts) with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). Second-line therapies appeared more successful in arm A compared to arm B. The impact of primary tumor location on this observation is unclear. Methods: Pts. were stratified for primary tumor site (left- vs. right-sided). Duration of 2nd-line therapy was calculated as time from first to last application. Progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) were evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression. All analyses were performed in the RAS wild-type population of the trial and reported according to drug sequences. Results: 272 of 400 pts. (68%) received 2nd-line therapy, of those 206 (109 in arm A, 97 in arm B) pts. presented left-sided, whereas 66 (26 in arm A, 40 in arm B) pts. presented right-sided primaries. PFS2nd was markedly longer in pts. with left-sided as compared to right-sided primary tumors (6.0 (95% CI: 5.5-6.7) vs. 3.4 (95% CI: 3.0-5.8) months, hazard ratio (HR): 0.64 (95% CI: 0.47-0.87), P = 0.005). Differences in PFS2nd between study-arms were evident in pts. with left-sided primaries (arm A: 7.3 (95% CI: 6.4-7.7) vs. arm B: 5.3 (95% CI: 4.3-5.9) months, HR: 0.61 (95% CI: 0.44-0.84), P = 0.002), but not in pts. with right-sided primaries (arm A: 4.0 (95% CI: 3.0-6.3) vs. arm B: 3.3 (95% CI: 2.6-5.8) months, HR: 1.09 (95% CI: 0.62-1.90). Consistent observations were also made for treatment duration and OS2nd. Conclusions: This retrospective analysis indicates that treatment duration and efficacy of second-line therapy are associated with primary tumor location. Efficacy of second-line therapy was significantly greater in pts. with left-sided tumors as compared to right sided tumors. This difference was driven by superior activity of second-line regimens of arm A compared to arm B in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in mCRC across treatment lines. Clinical trial information: NCT00433927.