bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of expanded BRAF mutational status on the outcome for metastatic colorectal cancer patients with anti-EGFR antibody: An analysis of the BREAC trial (Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics).
Authors: Yamazaki Kentaro , Yoshino Takayuki , Tsuchihara Katsuya , Shinozaki Eiji , Muro Kei , Nishina Tomohiro , Yamaguchi Kensei , Akagi Kiwamu , Yuki Satoshi , Yamanaka Takeharu , Nomura Shogo , Fujii Satoshi , Esumi Hiroyasu , Abe Yukiko , Ohtsu Atsushi
Published: February 2017

573

Background: BRAFV600E mutation has been recognized as a prognostic marker in patients (pts) with metastatic colorectal cancer (mCRC). Several studies have consistently shown a significant association between the presence of BRAFV600E mutation and resistance to anti-EGFR antibody therapy in pts with previously treated mCRC while there are few reports on the clinical impact of minor BRAF mutations. Methods: The BREAC trial was a multicenter, retrospective study to investigate the novel biomarkers of anti-EGFR antibody therapy. RAS and BRAF mutations were detected by targeted sequencing using FFPE materials of mCRC pts who received anti-EGFR antibody after a failure to standard therapies. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were evaluated according to expanded RAS/BRAF mutational status. Results: Of 184 pts enrolled in the study, RAS/BRAF testing was succeeded in 150 pts. Patients characteristics were as follows; male/female 87/63, median age 63.5 years (range, 28-85), PS 0/1/2 81/65/4. Median PFS, OS, and RR were 4.0 months, 12.4 months, and 21%, respectively. Expanded RAS and BRAF mutations were detected in 40 pts (26.7%, KRAS/NRAS 29/11) and in 16 pts (10.7%, BRAFV600E/other 9/7), respectively. Observed BRAF mutations other than BRAFV600E were located at kinase domain. The clinical outcomes of other BRAF mutations were worse similar to those of BRAFV600E and expanded RAS mutations (Table). Conclusions: Expanded BRAF mutations might predict a lack of response for mCRC pts who received anti-EGFR antibody. Further investigation is warranted to confirm the clinical impact of expanded BRAF mutations. [Table: see text]
Regional variation in physicians’ awareness, understanding, and use of personalized medicine in the treatment of cancer and perception of patient (pt) education.
Authors: Ciardiello Fortunato , Seufferlein Thomas , Tabernero Josep , Taieb Julien , Moiseyenko Vladimir , Ma Brigette , Lopez Gustavo A. , Esser Regina , Adams Richard A.
Published: February 2017

574

Background: A multinational survey of oncologists was conducted to assess the awareness and use of biomarkers in clinical practice (Ciardiello et al, ESMO 2014). These data explore regional variations as well as perceived level of “cancer literacy” among pts. Methods: Ten-minute online interviews were conducted with practicing oncology specialists (3 to 35 years of experience, treating > 15 pts/month) from 12 representative countries in Europe, South America, and Asia. Results: In total, 895 interviews were completed; numerous regional differences were observed. While most physicians use biomarkers (90%), there were marked regional variations. KRAS was the most frequent test. Among the 10% of physicians not using biomarkers, local availability of testing, speed of obtaining results, and cost were cited as the main reasons. The majority of Chinese doctors indicated that physician training (82%) and better biomarker information for pts (83%) would enable them to use biomarkers more often (global averages: 38% and 34%, respectively). Striking variation was seen in physicians’ assessment of pts’ knowledge of cancer biology, treatment options, use of biomarkers, and involvement in their own treatment plans. Only 38% of German physicians believed their pts know that tumors can be tested to help decide which treatment to give (global average: 73%). Only 21% of Saudi Arabian physicians believed the treatment decision process is shared between the doctor and/or multidisciplinary team and pt (global average: 82%). While physicians felt specialist nurses were the best source of information for pts, only 45% globally believed pts had access to these nurses (ranging from 19% in Russia to 83% in the UK). Conclusions: These data demonstrate wide global use of biomarkers but with regional variations reflecting cultural and local practice. Perception of pt cancer literacy and pt access to information also differs widely. Most physicians agree, however, that pts require more information to understand their disease better and become involved in treatment decisions.
Factors influencing the number of retrieved lymph nodes (LNs) in patients with stage II colon cancer: LN size and areas of B cells and T cells.
Authors: Okada Kazutake , Sadahiro Sotaro , Saito Gota , Tanaka Akira , Suzuki Toshiyuki , Kamijo Akemi
Published: February 2017

577

Background: In patients with stage II colon cancer, a high number of retrieved LNs has been reported to be associated with better outcomes. We examined the association between a high number of retrieved LNs and the presence of large mesenteric LNs and we evaluated the areas occupied by the T-cell and B-cell fields in LNs with large diameters. Methods: The study group comprised 320 patients with stage II colon cancer who underwent R0 resection from 1991 to 2003. The long- and short-axis diameters of 4,745 LNs were measured with a digitizer on specimens stained with hematoxylin and eosin. A LN with the largest long-axis diameter was selected for each patient and stained immunohistochemically using CD3 as a marker of T cells and CD20 as a marker of B cells. The CD3-positive and CD20-positive area ratios were evaluated, respectively. Results: The mean number of retrieved LNs was 15±10 per case. The correlation coefficients between the numbers and the long-axis diameters of LNs were as follows: mean 0.23, median 0.16, maximum 0.59, and minimum -0.29. The correlation coefficients between the numbers and short-axis diameters were 0.18, 0.13, 0.54, and -0.33, respectively. The correlation coefficient was highest for the maximum long-axis diameter. When the maximum diameter was divided at 5-mm intervals, the number of LNs significantly increased in parallel to an increase in the maximum long-axis diameter (p<0.001). The median follow-up was 119 months. Fifty-six patients (18%) had recurrence, 110 (34%) died of all causes, and 48 (15%) died of colon cancer. On survival analysis, age, T stage, and maximum long axis diameter of LNs were independent prognostic factors. The CD20 area ratio was significantly higher in LNs with a long-axis diameter of 10 mm or greater (0.44±0.09) than in LNs with a long-axis diameter of less than 10 mm (0.41±0.10, p=0.018). There were no differences in the CD3 area ratio. Conclusions: In stage II colon cancer, the number of retrieved LNs correlated with the maximum long-axis diameter of LNs. The long-axis diameter as well as age and T stage were independent prognostic factors. LNs with a larger long-axis diameter had a significantly increased intranodal B-cell area ratio.
A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer.
Authors: Janjigian Yelena Yuriy , Ku Geoffrey Yuyat , Ilson David H. , Boyar Michelle S. , Capanu Marinela , Chou Joanne F. , Kelsen David Paul , Imtiaz Tooba , Berger Michael F. , Vakiani Efsevia
Published: February 2017

59

Background: Trastuzumab combined with chemotherapy is the standard of care for pts with HER2+ EG cancer. Resistance to trastuzumab clearly emerges in this population. Afatinib, a potent ErbB Family Blocker, induced tumor regression in MSKCC HER2+ patient derived xenografts (PDX). This study assesses safety and preliminary efficacy of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma, after progression on trastuzumab, received oral afatinib 40 mg daily. Archival pre-trastuzumab tissue, tumor biopsy after progression on trastuzumab and after 1 week on afatinib is mandated on protocol for next generation sequencing (NGS), proteomics and establishment of PDX. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 20 pts treated with afatinib; median age 61, KPS 80; median 2 (1 to 4) prior trastuzumab regimens, 67% of tumors IHC3+; 33% IHC2+/FISH>2.0. Common adverse events included: rash or dry skin (Grade 1/2:80%), diarrhea (Grade 1/2:60%), nausea/vomiting (grade 1/2:40%) fatigue (grade1/2: 25%). To date, 19 pts evaluable for response, 2 PRs and 6 SD, 42% disease stabilization rate (PR+SD) at 4months (4 to 13 mos). PDXs established from biopsies of 7 pts. EGFR amplification was detected in the tumor of 2 pts with PRs and 1 of 6 pts with SD. Recurrent PIK3CA, ERBB3 and MTORmutations were observed. Conclusions: Afatinib shows clinical efficacy and is well tolerated in patients with trastuzumab refractory, heavily pretreated EG cancer. Enrollment has now begun in an afatinib + trastuzumab cohort. Efforts to elucidate the mechanisms of trastuzumab resistance including validation of potential drivers of trastuzumab resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
Comprehensive analysis of predictive biomarkers for patients with curative colorectal cancer patients and high risk of recurrence.
Authors: Mori Koichiro , Toiyama Yuji , Saigusa Susumu , Noguchi Tomofumi , Ide Shozo , Imaoka Hiroki , Uratani Ryo , Oki Satoshi , Fujikawa Hiroyuki , Hiro Junichiro , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , Inoue Yasuhiro , Tanaka Koji , Mohri Yasuhiko , Kusunoki Masato
Published: February 2017

607

Background: Preoperative serum systemic inflammatory response (SIR) has been reported in patients with various cancers including colorectal cancer (CRC) as predictive biomarker of early recurrence. Molecular phenotypes of CRC including microsatellite instability (MSI) status and tumor infiltrating lymphocytes (TILs) have also known to be associated with recurrence in curative CRC patients. We comprehensively evaluated SIR status, MSI status and TILs in curative CRC patients and investigated which can be promising as high risk markers of recurrence in these patients. Methods: This retrospective study enrolled 157 CRC patients with stage I-III undergoing curative operation for whom preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and CRP were available as indicators of SIR status. For analysis of molecular phenotypes, we evaluated TILs by counting the number of intra-tumor Foxp3 and CD8 positive T cells by IHC analysis. Next, MSI status was determined in using 5 mononucleotide repeat microsatellite markers. Finally, we investigated the impact of SIR status, TILs and MSI status on the recurrence of these patients. Results: This study included a total of 90 males and 67 females, with an average age of 66.9 years. Twenty-nine patients (18.4%) developed recurrence. Kaplan-Meier analysis using SIR indicators revealed that patients with high CRP, NLR and PLR levels were significantly poorer disease free survival (DFS) than those with low levels. Low infiltrating CD8-positive T cells were significantly predictive factors for poor DFS, but there was no correlation between MSI status and recurrence, In univariate analysis, low infiltrating CD8-positive T cells, high CEA, CRP, NLR and PLR levels in serum were significantly predictive factors for poor DFS, respectively. Multivariate analysis showed that low infiltrating CD8-positive T cells and high serum CRP levels were independent predictive markers for recurrence in curative CRC patients. Conclusions: We demonstrated that evaluation of both CRP levels in preoperative serum and tumor infiltrating CD8 lymphocytes in CRC tissues are useful to predict the curative CRC patients with early relapse.
Recurrence score distributions in stage II colon cancers of African American (AA) and Caucasian (CA) patients.
Authors: Govindarajan Rangaswamy , Posey James , Chao Calvin Y. , Lu Ruixiao , Jadhav Trafina , Javed Ahmed Y. , Javed Awais , Mahmoud Fade A. , Osarogiagbon Raymond U. , Manne Upender
Published: February 2017

613

Background: The 12-gene colon cancer assay (Oncotype DX) can identify groups of stage II colon cancer patients with lower or higher recurrence risk, but distribution of scores based on race/ethnicity has not been assessed. This study compared the distribution of Recurrence Score results and gene expression profiles between African American (AA) and Caucasian (CA) stage II colon cancer patients. Methods: Stage II colon cancer patients were identified from tumor registry data from four institutions: University of Arkansas for Medical Sciences, Little Rock; Veterans Administration Medical Center, Little Rock; Baptist Medical Center, Memphis, and University of Alabama at Birmingham. The 12-gene assay and mismatch repair (MMR) status were performed on formalin-fixed paraffin-embedded tissues by Genomic Health (Redwood City, CA). T-test and Wilcoxon test were used to compare data from the two groups (SAS Enterprise Guide 5.1). Results: Of the 244 subjects, there were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median ages (years) were 66 for AAs and 68 for CAs. Age, gender, surgery year, pathologic T-Stage, tumor location, number of nodes examined, lympho-vascular invasion, and MMR status were not significantly different between groups (p>0.05). Recurrence Score results between AAs (mean 27.9; SD 12.8) and CAs (mean 28.1; SD 11.8) were not statistically different (p>0.05). The proportion of patients with high Recurrence Score values (≥41) was similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups, (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC3 and GADD45B) was significantly different between the racial groups (p>0.05). After controlling for clinical and pathologic covariates, means and distributions of Recurrence Score and gene expression profiles still showed no statistical significance between racial groups (p>0.05). Conclusions: In a cohort of AA and CA stage II colon cancer patients with similar clinical characteristics, the distribution of Recurrence Score results and gene expression data were similar between AA and CA patients.
The role of inflammatory monocytes in human metastatic colorectal cancer.
Authors: Grossman Julie G. , Nywening Timothy M. , Belt Brian , Pittman Elizabeth , Giorgi Andrew , Michael Ahlers , Hawkins William G. , Strasberg Steven M. , Goedegebuure Peter S. , Fields Ryan C. , Linehan David
Published: February 2017

624

Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. 60% of CRC patients are diagnosed with metastatic (m) CRC and the 5-year survival is <20%. Myeloid cells, particularly inflammatory monocytes (IM), are recruited from the bone marrow to the tumor microenvironment where they become tumor associated macrophages and play a crucial role in tumor progression, metastasis, and chemoresistance. While the importance of IM have been shown in other malignancies, little is known about their role in human CRC. Methods: Human tissue was collected under an IRB approved protocol at Washington University. Flow cytometry was performed on PBMCs and single cell suspensions of normal tissue and tumor samples. Qualitative RT-PCR and confocal microscopy were performed for CCL2. T-cell suppression assays were performed using CD14+ IM isolated from patient peripheral blood and tumor samples. Results: Analysis of pre-operative blood revealed that monocyte levels correlate with the extent of disease burden. Monocytes were elevated in CRC patients compared with controls (p<0.0001), additionally patients with liver metastasis had further elevation in monocytes compared with patient’s with primary disease (p=0.01). In metastatic patients, monocyte levels also correlate with survival following resection of hepatic metastasis (p=0.0002). FACS analysis confirmed these findings and demonstrated that the circulating CD11b+/CD14+/CCR2+ subset of IM was responsible for the increase. Both primary CRC and liver mCRC had increased expression of CCL2 compared to uninvolved tissue (p=0.008 and p=0.03, respectively). Production of CCL2 was localized to CRC cells. FACS analysis showed CCR2+ tumor infiltrating macrophages were elevated in CRC liver metastasis compared to adjacent normal liver and a paucity of effector T-cells. CD14+ TAMs isolated from mCRC inhibited T-cell proliferation, illustrating the immune suppressive phenotype of these cells. Conclusions: Inflammatory monocytes correlate to prognosis in mCRC. Therefore, targeting CCR2+ myeloid cells may improve anti-tumor immunity and patient survival in metastatic disease.
Phase II pharmacodynamic trial of palbociclib in patients with KRAS mutant colorectal cancer.
Authors: O'Hara Mark H. , Edmonds Christine , Farwell Michael , Perini Rodolfo F. , Pryma Daniel A. , Teitelbaum Ursina R. , Giantonio Bruce J. , Damjanov Nevena , Lal Priti , Feldman Michael D , Zhang Paul J. , Mankoff David A. , Gallagher Maryann , DeMichele Angela , Vaughn David J. , O'Dwyer Peter J.
Published: February 2017

626

Background: Cell cycle dysregulation is a hallmark of most cancers. At the G1/S transition, cyclin dependent kinase (CDK) 4 and CDK 6 proteins associate with cyclin D proteins to allow cell cycle progression. Tumor cells that are driven by abnormalities of the cell cycle through activation of the cdk4/6-cyclin D axis showed increased phosphorylation of retinoblastoma protein (Rb), the major substrate for CDKs at the G1/S transition. Palbociclib is a potent specific inhibitor of cdk 4/6, with preclinical data showing G1 arrest in Rb-positive cells. Since activation of the MAP kinase pathway impacts directly on cdk-cyclin activation, we performed a phase II trial of palbociclib in patients with metastatic, KRAS-mutant colorectal cancer (mCRC). Methods: We screened 36 patients with KRAS mutant mCRC for Rb expression and 35 (97%) were Rb positive. We enrolled 15 patients, 9 (60%) of which were male and 6 (40%) female, median age was 62, 10 (67%) colon, 4 (27%) rectal (27%) rectal, and 1 (7%) appendiceal malignancy. Patients received 125mg daily of palbociclib for 21 days of a 28-day cycle, the recommended phase II dose. Results: Six patients (33%) experienced grade 3 neutropenia, 1 patient had grade 3 neutropenic fever (6%), and 2 patients (11%) had grade 3 AST/ALT elevation. There were no responses, but 5 patients (33%) had stable disease by RECIST criteria after 2 cycles of treatment, and 1 patient had stable disease for 8 cycles. The median number of cycles was two. As a pharmacodynamic marker of activity, 9 patients underwent FLT-PET at baseline and after 1 cycle of therapy. FLT-PET uses the tracer 3’-deoxy-3’[18F]-fluorothymidine, uptake of which is proportional to cellular proliferation. Six of the 9 patients (67%) had a decrease in uptake in target lesions, with an average 20% decrease in uptake in target lesions. FLT uptake in the bone marrow decreased by an average 4.85% and this correlated with a decrease in absolute neutrophil count of 62.3% (r2 0.59). Conclusions: While palbociclib has limited activity in KRAS mutant mCRC as a single agent, there is a clear pharmacodynamic effect as determined by FLT-PET imaging. Given the limited toxicity profile, combinations with non-myelosuppressive agents hold great promise. Clinical trial information: NCT01037790.
Colorectal cancer (CRC) cohort analysis of patients treated with buparlisib in a distinctive tissue-agnostic trial model for molecularly preselected tumors.
Authors: Piha-Paul Sarina Anne , Knost James A. , Nikolinakos Petros , Schwartzberg Lee Steven , Yardley Denise A. , Slosberg Eric Daniel , Kang Barinder , White Theresa , Lebedinsky Claudia
Published: February 2017

644

Background: This is a CRC cohort analysis from the novel Novartis “Signature” program of tissue-agnostic, genetic alteration specific signal-finding protocols. Potential patients are identified via standard-of-care profiling; we bring the ‘Protocol to the Patient’, with rapid start-up process. Buparlisib (BKM120) is an oral pan-PI3K inhibitor evaluated in this program. Methods: Patients had progressive/relapsed CRC harboring PI3K pathway activated tumors, measurable disease, ECOG PS ≤1, and adequate organ function. A local CLIA-certified test is sufficient for eligibility. Central post hoc broad tumor molecular profiling of genetic alteration is performed. BKM120 was given orally (100 mg) qd. The primary objective is to assess clinical benefit (SD or better at 16 weeks). Statistical design adaptively clusters patients into cohorts for independent analysis for early futility or efficacy. Results: 18 CRC patients were dosed: 10 females, 15 Caucasian, median age 58 years (40-80), all had ECOG PS ≤1. Median prior therapies: 4 (1-13). Actionable alterations present at baseline (local): 10 (55.6%) PIK3CA mutation, 4 (22.2%) PTEN loss (IHC), 3 (16.7%) each PTEN mutated and PIK3R1 mutated. Median time on study was 5.1 weeks (1-16). Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8. Central genomic profiling: DNA from 14 patients was assessed covering a panel of 288 cancer genes. All patients had a mutation in APC, 10 (71%) also had KRAS mutations and 11 (79%) had mutations in TP53. Three patients with the lowest PFS exhibited mutations in ERBB2 and ERBB4. Concordance between local and central lab results was 73%. Conclusions: This program facilitated the enrollment of molecularly profiled CRC patients with PI3K pathway alterations. In this cohort, BKM120 had a manageable safety profile with negligible activity as single agent. Further evaluation can determine the effect of BKM120 in combination with other agents. NCT01833169 Clinical trial information: NCT01833169.
Irinotecan (Iri) and buparlisib (B) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Baranda Joaquina Celebre , Reed Greg , Williamson Stephen K. , Perez Raymond P. , Stoltz Maxine L. , Mackay Chris , Madan Rashna , Pessetto Ziyan Y. , Godwin Andrew K.
Published: February 2017

655

Background: The PIK3CA pathway has oncogenic role in mCRC. Buparlisib is an oral pan-class PIK3CA inhibitor. It is currently being studied in combination trials for various malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus B in pts with previously treated mCRC, with or without previous Iri therapy. We also performed PK analysis of each drug alone and in combination, determined clinical response to the combination, and evaluated achieval FFPE samples for somatic mutations in a panel of cancer associated genes, including PIK3CA for clinical correlation. Methods: A 3+3 dose titration method was used. Iri was administered intravenously every 14 days (one cycle) and B orally daily. Pts received the first dose of Iri on Cycle1 Day1. B was started 24 hours after the first dose of Iri. Safety and toxicity assessments were performed every cycle. Results: Twenty patients were enrolled: 4 in cohort 0 (Iri 120 mg/m2 + B 50 mg/d), 11 in cohort 1 (Iri 150 mg/m2 + B 50 mg/d), 5 in cohort 2 (Iri 150 mg/m2 + B 80 mg/d). The most common Grades 3/4 adverse events were neutropenia and abdominal pain. The MTD was Iri 150 mg/m2 + B 50 mg/d. The DLTs include male genital mucositis, grade 3 diarrhea, and asymptomatic grade 3 hyponatremia. In cohort 1, one pt experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were seen. There is no significant change in the PK of Iri between Cycles 1 and 2. B at 50 mg had no consistent effect on the disposition of Iri given at 120 mg/m2 and 150 mg/m2. The Cmax and AUC for B show clear dose proportionality. Using targeted re-sequencing, a 48-gene panel that included AKT1, BRAF, KRAS, and PTEN was performed. The complete analysis of the correlative study will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. However, it is too early to determine the activity of this combination in the treatment of mCRC. Clinical trial information: NCT01304602.
Nomograms for overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer (mCRC): Construction from 19,678 ARCAD patients.
Authors: Sjoquist Katrin Marie , Renfro Lindsay A. , Simes John , Tebbutt Niall C. , Clarke Stephen John , Meyers Jeffrey P. , Gonsalves Wilson I. , Adams Richard , Seymour Matthew T. , Saltz Leonard , Schmoll Hans , Sargent Daniel J. , De Gramont Aimery , Zalcberg John Raymond ,   on behalf of the Fondation Aide et Recherche en Cancérologie Digestive (ARCAD) Group
Published: February 2017

659

Background: Prospective survival prediction of patients with metastatic colorectal cancer is difficult. Prognosis estimation based on readily available clinicopathologic factors has the potential to inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for OS and PFS in mCRC using the multi-trial ARCAD database. Methods: Data from 19,678 mCRC pts accrued to 24 first line randomized phase III clinical trials since 1997 were used to construct and validate Cox models for PFS and OS, stratified by treatment arm within each study. Candidate variables included age, gender, BMI, performance status, colon vs. rectal cancer, prior chemotherapy, number of metastatic sites, sites of metastases (liver, lung, lymph nodes), and baseline bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil:lymphocyte ratio (dNLR). Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions considered if p<0.001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated using a 10% holdout sample from each trial. Results: Nomograms for OS and PFS including remaining variables were well calibrated with C-indices of 0.66 and 0.60, respectively. Evaluation of external validity revealed good concordance; 71% and 67% respectively between predicted (> vs. <50% probability) and actual (yes/no) 1-year OS and 6-month PFS, and median 1-year OS and 6-month PFS predictions fell within the actual 95% Kaplan-Meier intervals. Gender, liver and lung metastases, and dNLR were not prognostic for OS; prior chemo, colon vs. rectum, dNLR, liver and lymph node metastases, and gender did not predict for PFS. No clinically relevant pairwise interactions were identified. Conclusions: The proposed nomograms are well calibrated and internally and externally valid. These tools have the potential to aid prognostication and patient/physician communication, and balance risk in randomized trials in mCRC.
First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab (pmab) or bevacizumab (bev) in wild-type (WT) RAS metastatic colorectal carcinoma (mCRC): Tumor response outcomes beyond RECIST.
Authors: Rivera Fernando , Karthaus Meinolf , Hecht J. Randolph , Fasola Gianpiero , Canon Jean-Luc Re , Koukakis Reija , Terwey Jan-Henrik , Schwartzberg Lee Steven
Published: February 2017

660

Background: In the PEAK study, pmab + FOLFOX6 was associated with longer OS than bev + FOLFOX6 in first-line RAS WT mCRC. RECIST overall response rates (ORR) were similar between treatment arms. Here, we report exploratory analyses of tumour assessments beyond RECIST. Methods: PEAK was a randomised phase II study of first-line pmab + mFOLFOX6 vs bev + mFOLFOX6 in previously untreated mCRC. ORRs (investigator assessed), median duration of response (DoR; from first confirmed response to disease progression or death [secondary endpoint]) and depth of response (DpR; defined as the percentage of tumour shrinkage at nadir or progression) in RAS WT pts were calculated by treatment. Early tumour shrinkage (ETS) was defined as the proportion of patients with ≥30% tumour shrinkage at week 8 (exploratory analysis). Results: Overall, 169 pts withRAS WT mCRC were included in the ORR analysis and 154 had tumour-shrinkage data available at baseline and week 8. Significantly more pts in the pmab + mFOLFOX6 arm had ETS at week 8 vs. the bev + mFOLFOX6 arm (Table). ORRs were similar in the two arms, while DoR was significantly longer and DpR significantly greater with pmab + mFOLFOX6 (Table). ≥30% vs. <30% tumour shrinkage at week 8 was associated with longer median PFS (HR: 0.52 [95% CI: 0.29–0.92] and HR: 0.65 [95% CI: 0.38–1.13]) and OS (HR: 0.44 [95% CI: 0.15–1.32] and HR: 0.23 [95% CI: 0.08–0.66]) for pmab + mFOLFOX6 and bev + mFOLFOX6, respectively. Conclusions: Although ORR appeared to be similar or only numerically improved in the pmab arm of PEAK, the responses observed appeared to occur earlier, last longer and be deeper in our exploratory analyses. This is consistent with the observed OS and PFS benefit, and with data reported earlier from the FIRE3 study. Clinical trial information: NCT00819780. [Table: see text]
The impact of early tumor shrinkage on survival in WJOG4407G trial, a randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab in first-line treatment for metastatic colorectal cancer.
Authors: Nagase Michitaka , Yamazaki Kentaro , Tamagawa Hiroshi , Ueda Shinya , Tamura Takao , Murata Kohei , Tsuda Takashi , Baba Eishi , Tsuda Masahiro , Moriwaki Toshikazu , Esaki Taito , Tsuji Yasushi , Muro Kei , Taira Koichi , Denda Tadamichi , Ando Masahiko , Morita Satoshi , Boku Narikazu , Hyodo Ichinosuke ,   West Japan Oncology Group
Published: February 2017

679

Background: Early tumor shrinkage (ETS) has been reported as an important predictor of favorable outcomes in patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy. We investigated the impact of ETS on survival in a randomized phase III study (WJOG4407G), which directly compared mFOLFOX6+bevacizumab (Bev) with FOLFIRI+Bev as first-line treatment. Methods: The subjects of this study were patients with measurable lesions whose tumor responses at 8 weeks were evaluated. ETS was defined as 20% or more decrease in the sum of the longest diameters of target lesions (RECIST ver.1.0) at 8 weeks. Progression-free survival (PFS) and overall survival (OS) were compared between patients with ETS and without ETS in each treatment. Results: Of 402 patients enrolled in the WJOG4407G trial, 354 (mFOLFOX6+Bev/FOLFIRI+Bev 175/179) patients were evaluated for this analysis. In this population, response rate, median PFS, and median OS of mFOLFOX+Bev/FOLFIRI+Bev were 65.7/68.2%, 10.7/12.1 months (HR 0.916, 95%CI 0.725-1.157, p=0.281), and 28.9/31.9 months (HR 0.870, 95%CI 0.653-1.159, p=0.272), respectively. One hundred (57.1%)/113 (63.1%) patients in the FOLFOX+Bev/FOLFIRI+Bev groups achieved ETS. No significant difference of the ratio of the patients with ETS between both groups was observed (p=0.099). In the FOLFIRI+Bev group, both PFS and OS were significantly longer in patients with ETS than those without ETS while there were no remarkable differences in the mFOLFOX6+Bev group (see Table). Conclusions: There were substantial differences in PFS and OS between the patients with and without ETS in the FOLFIRI+Bev group, but not in the FOLFOX+Bev group. The impact of ETS on survival is suggested to be different according to chemotherapy regimens. Clinical trial information: UMIN000001396. [Table: see text]
Maintenance therapy with the TLR-9 agonist MGN1703 in the phase II IMPACT study of metastatic colorectal cancer patients: A subgroup with improved overall survival.
Authors: Schmoll Hans-Joachim , Riera-Knorrenschild Jorge , Kopp Hans-Georg , Mayer Frank , Kroening Hendrik , Nitsche Dieter , Kuhlmann Jan , Ziebermayr Reinhard , Andel Johannes , Arnold Dirk , Schmidt Manuel , Wittig Burghardt , Scheithauer Werner
Published: February 2017

680

Background: Patients with mCRC and disease control after induction with first-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase II IMPACT trial, aiming to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after first line induction therapy in mCRC. Methods: The trial was prematurely closed after randomization of 59 patients. The final analysis showed a superior effect of MGN1703 compared to placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p=0.041) and 0.56 (p=0.070) by local investigator assessment or independent radiological review, respectively. Exploratory PFS analyses of pretreatment characteristics identified patients with normalized CEA, objective response, and the presence of activated NKT cells at the end of induction chemotherapy to benefit the most from maintenance with MGN1703. We analysed the impact of these factors on the secondary endpoint overall survival (OS). Results: At time of final study analysis, OS data were not mature. Only 35% of MGN1703 patients had an event, as opposed to 50% of placebo patients. The HR for OS of whole study population was 0.63 (median 22.6 vs. 15.1 months, p=NS). The subgroup of patients randomized into the study with confirmed RECIST response had a HR of 0.40 (median 24.5 vs. 15.1 months, p=NS), suggesting this may be the population with greater benefit. HR for patients with normalized CEA or with activated NKT cells were 0.69 and 0.43, respectively. Based on this evidence, in the phase III IMPALA study patients with objective response after standard induction therapy are randomized to standard treatment or switch maintenance with MGN1703. CEA and activated NKT cells are stratification factors for the study and will be prospectively assessed. Conclusions: The pretreatment characteristics predictive of a PFS benefit in the IMPACT study seem to retain their value also in exploratory analyses for OS. This information has been used to design the phase III IMPALA study, currently recruiting patients. Clinical trial information: NCT01208194.
A phase III study of xilonix in refractory colorectal cancer patients with weight loss.
Authors: Fisher George A.
Published: February 2017

685

Background: Xilonix, an anti-interleukin-1α true human monoclonal antibody is being assessed as cancer therapy to improve overall survival (OS) in advanced colorectal cancer (CRC) patients. Methods: An open label multicenter randomized comparator controlled study to evaluate efficacy and safety of Xilonix in CRC complicated with cachexia. Eligible patients had metastatic CRC, failed oxaliplatin or irinotecan based chemotherapy, and lost ≥5% total body weight in the previous 6 months (m). Patients were 1:1 randomized to Xilonix (3.75 mg/kg intravenously every two weeks) or megestrol acetate (MA, oral 800 mg daily) until progression. Primary endpoint was OS. Secondary endpoints included assessment of patient well-being using the EORTC QLQ-C30 questionnaire. Platelets support tumor growth and metastasis and platelet counts increase during cancer progression. IL-1α on platelets may be a target of Xilonix and thus platelet count was a key pharmacodynamic measure. Results: 40 patients were enrolled between March 2013 and July 2014, at which time the study was halted to revise inclusion criteria to reduce screen failures. An eligibility violation excluded 1 Xilonix patient from analysis (Xilonix n=19, MA n=20). MA treatment arm had a 39% shorter median OS (2.0 versus 2.8 months) and a trend in increased risk of death (hazard ratio 2.17, p=0.17). Physical and role function worsened in patients receiving megesterol (median change of -13.3 (p=0.02), -16.7 (p=0.02) respectively), whereas in Xilonix treated patients these functions did not decline during therapy (median change 0, p=0.88 and 0, p=0.69, respectively). Xilonix patients had treatment-related reduction in platelets compared to the MA group (median -60,000/mm3, vs 10,000/mm3, p=0.03). No infusion reactions, no discontinuations due to adverse events (AEs) and no related SAEs were reported for Xilonix. Conclusions: The trend in OS for Xilonix patients was encouraging and consistent with improved function and intended pharmacodynamic activity. An amended Phase III protocol has been developed to simplify enrollment for an ongoing study of Xilonix in an advanced CRC population. (NCT01767857) Clinical trial information: NCT01767857.
Results of functional testing and pharmacokinetics comparing ABP 215 to bevacizumab.
Authors: Markus Richard , Kaur Primal , Chow Vincent , Zhang Nan , Born Teresa , Huynh Quyen , Maher Gwen , Velayudhan Jyoti , Howard Monique , Reynhardt Kaz , Goletz Theresa
Published: February 2017

711

Background: ABP 215 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). Biosimilar mAbs are likely to have differences in product quality attributes due to different expression systems, bioprocess and purification, so demonstration of functional similarity and pharmacokinetic (PK) equivalence is the foundation for biosimilarity. Objectives: To assess functional similarity and PK equivalence of ABP 215 and BEV sourced from EU and US. Methods: Functional similarity testing included binding to VEGF and VEGF isoforms by surface plasmon resonance and to FcRn and FcγRIIIa. Inhibition of proliferation and VEGFR2 autophosphorylation was compared in endothelial cells. PK equivalence was evaluated in a randomized, single-dose, 3-arm study in healthy adult male subjects. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (Cmax). Secondary endpoints were safety, tolerability, and immunogenicity. Results: ABP 215 and BEV (EU) are functionally similar as previously presented. Binding affinity to VEGF was similar between ABP 215 (117 pM) and BEV (US) (126 pM) as was binding to VEGF165 and VEGF121. Binding to FcRn was similar between ABP 215 (95-102%) and BEV (96-111%). Binding to FcγRIIIa was also similar; ABP 215 (108-115%) and BEV (85-93%). Potency in proliferation inhibition was similar between ABP 215 (91-97%) and BEV (91-96%), as was inhibition of autophosphorylation. After a single dose, geometric mean (GM) of Cmax and AUCinf for ABP 215 were 87.2 µg/mL and 29,400 µg.h/mL, for BEV (US) were 89.1 µg/mL and 29,600 µg.h/mL, for BEV (EU) were 84.7 µg/mL and 30,600 µg.h/mL. The 90% CIs of GM ratio for Cmax and AUCinf were within pre-specified equivalence criterion of 0.80 to 1.25 confirming PK equivalence. There were no adverse events (AEs) or serious AEs leading to study discontinuation. Treatment-related AEs were reported for 22.1% in ABP 215, 16.4% in BEV (US) and 22.4% in BEV (EU) groups; no subjects developed anti-drug antibodies. Conclusions: ABP 215 is similar to BEV in sensitive functional tests and equivalent to BEV based on results of the phase 1 PK study.
The optimization of 5-fluorouracil (5FU) dose by pharmacokinetic (PK) monitoring in Asian patients with advanced-stage gastrointestinal (GI) cancer.
Authors: Soh I Peng Thomas , Mogro Maria Jannet , Soo Ross A. , Pang Angela , Tan Chee Seng , Chuah Benjamin , Zee Ying Kiat , Wong Andrea Li Ann , Ow Samuel Guan Wei , Sundar Raghav , Lim Joline Si Jing , Huang Yiqing , Ling Winnie Hui Yee , Yong Wei-Peng
Published: February 2017

770

Background: PK guided dose management and systemic plasma levels of 5FU have shown correlation with both reduced toxicity and improved efficacy. However, data for Asian patients are lacking. Levels are highly variable with doses based on body surface area. Methods: Area under the curve (AUC) was estimated using a nanoparticle immunoassay from Saladax Biomedical (My5-FU). Patients with GI cancers receiving de Gramont, FOLFIRI or mFOLFOX6 regimens had 5 PK sampling time points obtained (reduced to 2 samplings after first 15 patients). If target AUC (18-28 mg.h/L) was reached for 2 consecutive cycles, monitoring is performed for alternate cycles. With dose adjustments, PK sampling will be done in the next cycle. Results: 50 patients (33 males, 17 females) enrolled, with 349 PK samplings done, and 291 analyzable. 31 (62%) had mFOLFOX6, 18 (36%) FOLIRI and 1 (2%) de Gramont. Colorectal cancer (76%) and gastric cancer (12%) were the most common cancer types. Median AUC (35 evaluable) was 24.2 in C1, 23.65 in C2 (n=38), 20.6 in C3 (n=38) and 22 mg.hr/L in C4 (n=35). Proportion of patients achieving target AUC were 54.3%, 32%, 39.5% and 51% respectively and did not change significantly despite PK guided doses adjustments (C1 vs. C4 p=0.81, C2 vs. C3 p= 0.63, C2 vs. C4 p=0.085, C3 vs. C4 p=0.31). Higher than expected rate of G3/4 neutropenia (52%) and fewer mucositis (0%) and diarrhea (8%) were observed. Other toxicities (all grades) were fairly consistent with historical data. There were no inter-cycle differences in rates of toxicity, and no relationship with G3/4 toxicities and high AUC levels were observed. Correlation of response rates, efficacy with AUC were omitted due to heterogeneous tumor types. Conclusions: Contrary to past studies, PK guided 5FU did not result in a greater number of patients achieving target AUC in Asian patients. Furthermore, AUC levels of 5FU did not correlate with toxicity. Larger numbers are needed to confirm the clinical utility and benefit of PK guided 5FU in Asian patients. Clinical trial information: NCT00943137.
Association between single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC) and clinical outcomes in advanced gastric cancer (AGC) patients (pts) treated with taxane-based chemotherapy.
Authors: Yamauchi Shinichi , Okazaki Satoshi , Barzi Afsaneh , Zhang Wu , Yang Dongyun , Cao Shu , Ning Yan , Sunakawa Yu , Stremitzer Stefan , Matsusaka Satoshi , El-khoueiry Rita , Mendez Angela , Parekh Anish , Lenz Heinz-Josef
Published: February 2017

79

Background: Taxanes which disrupt the microtubule function and inhibit the process of cell division have shown encouraging activity in the treatment of AGC. Resistance to these agents often becomes a problem in clinical settings and its mechanism hasn’t been dissolved conclusively. SAC is a safety device ensures the proper chromosome segregation in mitosis and is required for taxane-induced cell death. We hypothesized genetic variants in SAC genes may be associated with clinical outcomes in pts with AGC treated with taxane. Methods: Genomic DNA was isolated from blood or tissue samples of 39 U.S. pts (median age 57; median follow-up 6.4 months) for evaluation set and 39 Japanese (JPN) pts (median age 63; median follow-up 9.4 months) for validation set, with AGC treated with taxane. Twenty-five functionally significant SNPs in SAC genes (MAD1, MAD2, BUB3, BUBR1, RAN, TPX2, CDC20, AURKA, AURKB, RCC1, ANAPC10, ANAPC13) were analyzed by PCR-based direct sequencing and evaluated for association with outcomes. Results: In univariate analysis, rs4236271 (MAD1), rs6954673 (MAD1), and rs2064863 (AURKA) showed a significant difference in 6-month (mo) progression-free survival (PFS) rate [(C/C 42%, C/T 12%; HR 2.66, P=0.008), (C/C 75%, C/T or T/T 24%; HR 5.10, P=0.008), and (T/T 50%, T/G 15%, G/G 57%; HR1.55, P=0.046), respectively] and 18-mo overall survival (OS) rate [(C/C 40%, C/T 8%; HR3.69, P<0.001), (C/C 56%, C/T or T/T 19%; HR3.60, P=0.004), and (T/T 59%, T/G 15%, G/G 29%; HR 2.02, P=0.047), respectively] in evaluation set. In multivariate analysis, rs4236271 and rs6954673 remained significant in PFS (HR 7.24, P=0.005, HR 14.49, P=0.015, respectively) and OS (HR 7.39, P=0.001, HR 6.37, P=0.002, respectively). In validation set, rs6954763 showed a significant difference in 18-mo OS rate (C/C 16%, C/T or T/T 47%, HR 3.55, P=0.014), but the impact of C/C genotype on OS in the JPN pts was the opposite to the U.S. pts. Conclusions: These results suggest that MAD1 polymorphisms may serve as a prognostic marker in pts with AGC. Further studies using larger population are needed to corroborate our results.
Lapatinib combined with ECF/x as first-line metastatic gastric cancer (GC) according to HER2 and EGFR status: A randomized placebo controlled phase II (EORTC 40071).
Authors: Moehler Markus Hermann , Schad Arno , Mauer Murielle E. , Messina Carlo G. M. , Mahachie John Jestinah. M. , Lang Istvan , Van Cutsem Eric , Freire João , Lutz Manfred P. , Roth Arnaud
Published: February 2017

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Background: ECF/X (epirubicin (E) + cisplatin (C) + 5-fluoruracil (F) or capecitabine (X)) is a reference chemotherapy (CT) regimen in metastatic GC. Trastuzumab with CF/X prolonged survival (OS) of metastatic HER2+ gastric or esophagogastric junction cancer (GC) patients (pts). Lapatinib (LAP) inhibits both, EGFR1 and HER2, and showed activity in phase II GC trials. This double-blind Phase II study prospectively addressed efficacy and safety of LAP with ECF/X in GC pts with discordant FISH or IHC HER2 status or EGFR1+. Methods: Pts without prior palliative CT, screened centrally for HER2/EGFR1 (by FISH and IHC) were enrolled into 3 strata: 1) HER2 FISH+ and IHC 2/3+, 2) HER2 FISH- and IHC 2/3+, or 3) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts without HER2 + or EGFR1+, by FISH or IHC, were excluded. Pts were randomized to LAP 1250mg (arm 1) or placebo (arm 2), with ECF or ECX (investigator-selected) for 6 cycles. Primary endpoint was progression free survival (PFS). Secondary endpoints were toxicity, response rates, OS, HER2 concordance and correlation of HER2/EGFR. Results: The trial was prematurely closed to patient accrual given the LOGIC trial results at ASCO 2013. A total of 69 pts were tested in central lab of whom 9 (13%), 5 (7.2%) and 25 (36.2%) were in stratum 1, 2 and 3. Of these, 28 patients (6/4/18) were randomized (14 in arm 1, 14 in arm 2) and followed up. Due to the low number of pts accrued, no formal statistical tests were carried out. No safety concerns were found in arm 1. No complete responses were seen. 6 pts had partial responses in arm 1 vs. 3 pts in arm 2. Median PFS was 7.1 months in arm 1 vs. 5.9 months in arm 2 (HR=0.94, 95% CI: 0.41-2.14) for all pts, and 6.2 months in arm 1 vs. 6.3 months in arm 2 (HR=0.99, 95% CI: 0.36-2.75) for stratum 3 pts, respectively. Median overall survival was 13.8 months in arm 1 vs. 10.1 months in arm 2 (HR=0.90, 95% CI: 0.35-2.27) for all pts. Conclusions: Lapatinib with ECF/X did not show appealing activity in EGFR+ metastatic GC patients in this small phase 2 trial. The combination was well tolerated. Clinical trial information: NCT01123473.