bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib.
Authors: Jeffers Michael , Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Grothey Axel
Published: February 2017

381

Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.
Relationship of EGFR-independent activation of PI3K in KRAS wild-type colorectal cancers and cetuximab resistance.
Authors: Corcoran Ryan Bruce , Ebi Hiromichi , Ryan David P. , Meyerhardt Jeffrey A. , Engelman Jeffrey A.
Published: February 2017

385

Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous inhibition of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody against EGFR that has been approved for treatment of metastatic colorectal cancer (CRC). Studies have suggested that its benefit is restricted to patients with KRAS wildtype (WT) CRC. However, even in KRAS WT CRC, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood. Methods: The ability of cetuximab to inhibit PI3K-AKT and MEK-ERK signaling in a panel of KRAS WT CRC cell lines was assessed by immunoblotting. Paired biopsies from CRC patients obtained pre-treatment and after 3 weeks of cetuximab were evaluated by immunohistochemistry and proteomic techniques to assess inhibition of PI3K activity. We preformed immunoprecipitations (IPs) of the regulatory subunit of PI3K from cell lines and primary CRCs to identify RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS WT CRC cell lines and xenograft models. Results: Cetuximab led to effective inhibition of MEK-ERK signaling (>75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS WT CRC cell lines tested. Analysis of paired biopsies from patients with KRAS WT CRC obtained pre-treatment and after 3 weeks of cetuximab demonstrated that the PI3K pathway remained active in many patients, despite cetuximab therapy. PI3K regulatory subunit IPs from cell lines and primary CRCs revealed multiple RTK inputs to PI3K, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and to tumor regressions in KRAS WT CRC xenograft models. Conclusions: Cetuximab fails to inhibit PI3K signaling in some KRAS WT CRCs. Additional RTKs other than EGFR play a role in PI3K activation in these cancers, which may contribute to cetuximab resistance. Combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS WT CRC, and should be evaluated in future clinical trials.
Immunohistochemical expression of receptor-tyrosine-kinase in patients with gastric cancer: A multicenter study in Japan.
Authors: Kimura Yutaka , Kurokawa Yukinori , Matsuura Nariaki , Fujita Junya , Imamura Hiroshi , Ebisui Chikara , Nushijima Yoichiro , Adachi Shinichi , Nishikawa Kazuhiro , Nishida Toshirou , Takiguchi Shuji , Mori Masaki , Doki Yuichiro
Published: February 2017

41

Background: Treatment of HER2 positive gastric cancer (GC) with trastuzumab, receptor-tyrosine-kinase (RTK) inhibitor, has led to significant gains in overall survival. Several other targeted therapies are currently undergoing preclinical and clinical testing in some malignancies and GC, directed against diverse oncogenic RTK, therefor it is important to define the expression pattern of target RTK in GC. A multicenter retrospective study was conducted to evaluate the correlation between the expression of some RTKs, HER2, EGFR and c-KIT, and clinicopathological features in GC. Methods: A total of 153 cases with GC which was surgically resected between 2000 and 2006 were registered from nine hospitals. The neoadjuvant treatment cases were excluded. Tumors were centrally examined for HER2, EGFR and c-KIT status with immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) for HER2. The relation between the expressions of HER2, EGFR and c-KIT and clinicopathological factors was examined by Fisher’s exact test. The hazard ratio (HR) for death was estimated, and overall survivals (OS) were compared between positive and negative cases of HER2, EGFR, and c-KIT using log-rank test. Results: The proportion of positive cases with IHC of HER2, EGFR and c-KIT was 7.8%, 14.4% and 11.1%, respectively. There was no significant correlation between the expression of HER2, EGFR and c-KIT and differentiation, location and depth. HER2-positive cases tended to be more frequent in differentiated type tumors. EGFR-positve cases were more frequent in lymph node metastasis (P=0.013). c-KIT-positive cases tended to be more frequent in T1-T2 tumors. OS in HER2-positive cases were clearly worse than in HER2-negative cases (HR 2.23 (95%CI, 1.16-4.38); P=0.014). EGFR-positive cases had a tendency to be worse than in EGFR-negative cases (HR 1.60 (95%CI, 0.94-2.71); P=0.082). c-KIT-negative cases were worse than in c-KIT-positive cases (HR 0.42 (95%CI, 0.17-1.02); P=0.048). Conclusions: This study showed that HER2 expression is a factor of poor prognosis and that EGFR-positive status and c-KIT-negative status tended to be associated with worse outcomes in resected GC.
PEAK (study 20070509): A randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild‑type (WT) KRAS metastatic colorectal cancer (mCRC).
Authors: Schwartzberg Lee Steven , Rivera Fernando , Karthaus Meinolf , Fasola Gianpiero , Canon Jean-Luc , Yu Hua , Go William Y.
Published: February 2017

446

Background: Pmab has demonstrated significant improvement in progression-free survival (PFS) in pts with WT KRAS mCRC as 1st-line tx in a phase III trial comparing pmab + FOLFOX4 vs FOLFOX4 alone. Here, we describe the results of PEAK, a multicenter, randomized phase II study evaluating pmab + mFOLFOX6 and bev + mFOLFOX6 in pts with previously untreated WT KRASmCRC. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg + mFOLFOX6 Q2W or bev 5.0 mg/kg + mFOLFOX6 Q2W. Pt eligibility criteria included: WT KRASmCRC, ECOG performance status ≤ 1, and no prior chemotherapy, anti-VEGF tx, or anti-EGFR tx for mCRC. The primary endpoint was PFS; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. No formal hypothesis was tested. Results: 285 pts with WT KRASmCRC were randomized and 278 pts received tx. Demographics were balanced between arms. Intent-to-treat efficacy results are shown (Table). Worst grade 3/4 adverse events (AE) occurred in 86% of pts in the pmab + mFOLFOX6 arm vs 76% of pts in the bev + mFOLFOX6 arm. Grade 5 AEs occurred in 5% of pts in the pmab + mFOLFOX6 arm and 6% of pts in the bev + mFOLFOX6 arm. Tx discontinuation due to any AE was 24% in the pmab + mFOLFOX6 arm and 27% in the bev + mFOLFOX6 arm. Conclusions: In this estimation study of pts with WT KRASmCRC without any prior therapy for mCRC, PFS and ORR were similar between arms. The median OS was not reached in the pmab + mFOLFOX6 arm. The safety profile for both arms was consistent with previously reported studies of either combination. Tx discontinuation rates due to AEs were similar between arms. Clinical trial information: NCT00819780. [Table: see text]
Bevacizumab (BEV) continued beyond first progression in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with BEV + chemotherapy (CT): Biomarker findings from ML18147.
Authors: Kubicka Stefan , Von Moos Roger , Greil Richard , Sastre Javier , Osterlund Pia J. , Arnold Dirk , André Thierry , Van Cutsem Eric , Mueller Thomas , Reyes-Rivera Irmarie , Bennouna Jaafar ,   on behalf of the ML18147 study investigators
Published: February 2017

452

Background: In ML18147, BEV + standard CT was continued as 2nd-line treatment for pts with mCRC progressing after 1st-line BEV + CT. ML18147 met its primary and secondary endpoints and had a comprehensive biomarker programme, including exploratory analyses of immunohistochemistry (IHC) and single nucleotide polymorphisms (SNPs). Methods: Tumour samples were analysed by IHC for VEGFA, VEGFR1, VEGFR2 and neuropilin-1; H-scores were generated. Tumor angiogenesis was determined by stereological analysis of CD31-stained microvessels; 183 SNPs of 30 mainly angiogenesis-related genes were genotyped. We assessed consistency of treatment effect point estimates, i.e. hazard ratios (HRs) on the same side of 1. Analyses were not adjusted for multiple testing or powered to detect statistically significant treatment by biomarker interactions. Results: IHC data were available for 213 pts (26% of ITT population) and SNP data for 274 pts (33% of ITT). There was no significant evidence of biomarker expression levels or their cellular localisation correlating with BEV treatment effect. Point estimates for a CD31 derivative (i.e. vessel or tumour area) suggested a trend for being predictive for overall survival (OS; HR 1.39 and 0.70 for CD31 derivative <median and ≥median, respectively), similar to data from previous studies. Other previously reported correlations (progression-free survival [PFS] with VEGFA and NRP1 in NO16966; OS with NRP1 in AVAGAST) were not seen. SNP analyses confirmed previous correlations for OS (VEGFA, VEGFR2) and suggested additional biomarker candidates (PFS: VEGFA, VEGFR1, VEGFR2, EGLN3; OS: VEGFR2, EGLN1). Five EPAS1 (HIF2α) SNPs were associated with BEV treatment effect, thus confirming previous findings of HIF2α SNPs as a predictive biomarker for BEV treatment effects. Conclusions: Exploratory IHC and SNP analyses in ML18147 revealed potential biomarker candidates for BEV in pts with mCRC. SNP analyses of angiogenesis-relevant genes were consistent with previous findings for a subset of SNPs, consolidating their role as potential predictive biomarkers of BEV treatment across indications. Clinical trial information: NCT00700102.
The influence of treatment response on the impact of resection margin status after preoperative chemoradiotherapy in rectal cancer.
Authors: Chie Eui Kyu , Lee Jooho , Kim Kyubo , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kang Gyeong Hoon , Han Sae-Won , Oh Do-Youn , Kim Tae-You , Bang Yung-Jue , Ha Sung W.
Published: February 2017

505

Background: Circumferential resection margin (CRM) and distal resection margin (DRM) have different impact on clinical outcomes after preoperative chemoradiotherapy (CRT) followed by surgery. Effect and adequate length of resection margin as well as impact of treatment response after preoperative CRT was evaluated. Methods: Total of 403 patients with locally advanced rectal cancer underwent preoperative CRT followed by total mesorectal excision between January 2004 and December 2010. After applying the criterion of margin less than 0.5 cm for CRM and/or less than 1 cm for DRM, 158 cases were included as a study cohort. All patients underwent conventionally fractionated radiation with dose over 50 Gy and concurrent chemotherapy with 5-FU or capecitabine. Median follow-up duration was 44.9 months. Results: The 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were 83.3%, 75.6%, 86.3%, and 77.4% respectively. CRM of 1.5 mm and DRM of 7 mm were cutting points showing maximal difference using maximal chi-square method. In univariate analysis, the shorter CRM was significantly related with worse clinical outcomes, whereas DRM was not. In multivariate analysis, CRM of 1.5mm, ypN, and perineural invasion were prognosticators for OS, DFS, LRFS, and DMFS. CRM was not a significant prognostic factor for good responders, defined as patients with near total regression or T down-staging. However, poor responders demonstrated a significant difference according to the CRM status. Conclusions: Close CRM, defined as 1.5 mm, was a significant prognosticator, but the impact was different for treatment response. Postoperative treatment strategy may be individualized based on this finding. However, findings from this study needs to be validated with larger independent cohort. [Table: see text]
Assessment of the impact of systemic chemotherapy (SC) on the quality of life (QOL) in patients with metastatic unresectable appendiceal epithelial neoplasms (AEN).
Authors: Eng Cathy , Choe Jennifer , Overman Michael J. , Fournier Keith F. , Phillips Jonathan , Baum George , Wolff Robert A. , Royal Richard E. , Mansfield Paul F. , Basen-Engquist Karen
Published: February 2017

522

Background: AEN is a rare malignancy ranging from indolent well-differentiated carcinoma to highly aggressive signet ring carcinoma. Optimal therapy is cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet some patients (pts) are suboptimal for CRS/HIPEC, and are considered for SC. We have previously reported our retrospective analysis suggesting overall survival (OS) benefits from SC. We then opted to assess the impact of SC on QOL in unresectable AEN pts for which no standard of care exists. Methods: 50 pts who initiated SC were prospectively enrolled at our institution between Oct. 2008 and Nov. 2011. EORTC (3.0) QLQ-C30 and QLQ-OV28 surveys were provided at baseline and quarterly for one year. Data were analyzed with Linear Fixed Effects models using SAS Proc Mixed. Baseline and 6 month follow-up scores were tested separately for all QOL outcomes. Subscale means were converted to scaled values from 0 to 100. Positive change over the interval indicated improvement, except in symptom scales where positive change indicated worsening symptomatology. Results: 26 pts (52%) were male, median age was 64 (37-80). All pts received 5-FU-based treatment, and 37 (74%) received a biologic agent. 18 pts (36%) had poorly differentiated histology. Statistically significant change was noted in 2 subscales (Table). Overall, the Global subscale demonstrated no significant change from baseline (MME=2.9095, p=0.4422). Conclusions: In light of the possible OS benefit of systemic treatment in unresectable AEN as previously presented, our data suggest that palliative SC does not decrease QoL and in fact correlates with improved emotional well-being, and diminished symptoms including myalgias, arthragias and weakness. Awareness of these clinical and psychiatric results will better enable clinicians to ensure optimal outcomes for their AEN patients while on treatment.[Table: see text]
Retrospective cohort study on the safety and efficacy of panitumumab for patients with metastatic colorectal cancer: The HGCSG1002 study—Analysis of adverse events.
Authors: Dazai Masayoshi , Fukushima Hiraku , Sato Yasushi , Yuki Satoshi , Ohnuma Hiroyuki , Okuda Hiroyuki , Tsuji Yasushi , Kawamoto Yasuyuki , Hatanaka Kazuteru , Iwanaga Ichiro , Koike Masahiko , Kato Takashi , Nakamura Michio , Sogabe Susumu , Fujikawa Koshi , Hosokawa Ayumu , Hisai Hiroyuki , Tateyama Miki , Sakata Yuh , Komatsu Yoshito ,   Hokkaido Gastrointestinal Cancer Study Group
Published: February 2017

554

Background: Panitumumab (Pmab) is a fully human monoclonal antibody specific to the epidermal growth factor receptor. It has been associated with very few infusion reactions, but has been pointed out more severe skin toxicity, compared to cetuximab which is a chimeric antibody.To evaluate the safety of Pmab for patients (pts) with metastatic colorectal cancer (mCRC) in daily clinical practice in Japan, retrospectively. Methods: Two hundred pts with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG1002 study). Adverse events were evaluated using Common Terminology Criteria for Adverse Events(CTCAE) Version 4.0. Results: Of 195 pts were able to evaluate for adverse events. Patients’ characteristics were as follows; male/female 112/83, median age 64 (range 40-82), ECOG performance status (0/1/2-) 103/71/21. Treatment line (1st/2nd/more than 3rd): 17/26/152. Grade 3 or higher adverse events related to Pmab were hypomagnesemia (11.5%), rash acneiform (14.3%), paronychia (4.6%). Adverse events accounted for 7.3% of pts discontinuation, but there were no treatment-related deaths. Grade 3 or higher hypomagenesaemia and rash acneiform were observed more often in more than 3rd line treatment, compared to 1st or 2nd line treatment (1st or 2nd/3rd-, 1/ 17, p=0.128, 2/26, p= 0.05). Conclusions: Severe hypomagnesemia was observed more often in daily practice in Japan, compared with previous reports. Grade 3 or higher hypomagnesemia and rash acneiform were observed more often in more than 3rd line setting, compared with 1st or 2nd line settings.
Cost-effectiveness of regorafenib for pretreated metastatic colorectal cancer patients in the United States.
Authors: Seal Brian S. , Özer-Stillman Ipek , Whalen John , Ambavane Apoorva , Yaldo Avin , Pawar Vivek
Published: February 2017

578

Background: There is an unmet need for treatments that provide a survival benefit for patients with heavily pretreated metastatic colorectal cancer (mCRC). In a randomized, double-blind, placebo-controlled trial, patients treated with regorafenib plus best supportive care (BSC) had significant improvement in overall survival (OS) versus patients in the placebo arm receiving BSC alone. The aim of this study was to estimate the cost-effectiveness of regorafenib for the treatment of patients with mCRC after failure or intolerance to irinotecan-, oxaliplatin-, and fluorouracil-based regimens, from the perspective of a U.S. health care payer. Methods: A cohort-partition model was developed to simulate treatment costs and survival for patients treated with regorafenib or BSC alone. Survival was projected by fitting Weibull distributions to trial data. Mean duration of treatment (3.0 months regorafenib, 2.1 months BSC), utilities (0.71 on treatment, 0.59 post-treatment) and serious adverse event rates were also based on trial data. Monthly drug monitoring and physician fee costs were based on Medicare fee schedules. Routine mCRC care and adverse event unit costs were obtained from an analysis of administrative claims in two large managed care databases. Costs were estimated in 2012 USD. Results: Patients treated with regorafenib had prolonged survival versus BSC alone (0.75 versus 0.60 years) and also had higher lifetime costs ($97,700 versus $59,494). The improvement in quality-adjusted life years (0.47 versus 0.37) was small due to the heavily pretreated nature of the patient population. The increase in costs was attributable to increases in costs for drug acquisition, adverse events , and routine care from increased survival. Conclusions: Regorafenib increases life expectancy for patients with pretreated metastatic colorectal cancer. The cost of this benefit could be considered high; however, it could be justifiable given high unmet need for these patients. The increase in cost is primarily due to drug acquisition costs, similar to other recent treatments for metastatic cancers.
The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.
Authors: Park Seong Joon , Ryu Min-Hee , Ryoo Baek-Yeol , Sohn Byeong Seok , Kim Ki-Hun , Oh Sung Tae , Yu Chang Sik , Yook Jeong Hwan , Kim Byung Sik , Kang Yoon-Koo
Published: February 2017

62

Background: Several retrospective studies have suggested that surgical resection of residual lesions could be beneficial if resection was done after disease control (partial response or stable disease) with imatinib in patients with metastatic or recurrent GIST. However, the benefit of surgical resection has not been proven yet compared to imatinib alone. Therefore, we compared the outcomes of surgical resection of residual lesions after imatinib (SI group) with those of imatinib alone (IM group) in patients with metastatic or recurrent GIST controlled with imatinib treatment. Methods: A total of 134 patients with metastatic or recurrent GIST who showed at least 6 months of disease stabilization or response to imatinib were included in this retrospective analysis. Patients were categorized into SI (n=42) or IM (n=92) group. To reduce the selection bias, propensity scores and inverse-probability-weighting (IPTW) adjustment were used in the outcome analysis. Results: Patient and tumor characteristics were statistically similar between SI and IM groups, except median age (51 in SI, 58 in IM, p=0.002), and metastases to peritoneum (12 in SI, 56 in IM, p=0.001). The patients in SI group underwent surgery of residual disease after a median 19.1 months of imatinib treatment (range, 7.2-87.0). With a median follow-up of 58.9 months (range, 15.4-129.1), progression-free survival (PFS) and overall survival (OS) were significantly longer in SI group than in IM group (PFS, 87.7 vs 42.8 months, p=0,001; OS, not reached vs 88.8 months, p=0.001). Multivariate analysis revealed SI group as well as female sex, KIT exon 11 mutation, and low initial tumor burden were associated with longer PFS, and SI group and low initial tumor burden were associated with longer OS. Even after applying IPTW adjustment, SI group showed significantly better outcome in terms of PFS (hazard ratio [HR], 2.326; 95% CI, 1.034-5.236; p=0.0412) and OS (HR, 5.464; 95% CI, 1.460-20.408; p=0.0117). Conclusions: This study strongly suggests that surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.
Randomized phase II study comparing dose-escalated weekly paclitaxel (wPTX) versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).
Authors: Takahari Daisuke , Shitara Kohei , Yuki Satoshi , Nakamura Michio , Kondo Chihiro , Tsuda Takashi , Kii Takayuki , Tsuji Yasushi , Utsunomiya Setsuo , Ichikawa Daisuke , Hosokawa Ayumu , Ishiguro Atsushi , Matsuo Keitaro , Oze Isao , Muro Kei
Published: February 2017

64

Background: wPTX is one of the standard second-line chemotherapies for AGC. Meanwhile, retrospective analysis of neutropenia during wPTX showed better overall survival (OS) among patients with neutropenia compared to patients without neutropenia. Therefore, we conducted randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated AGC. Methods: Patients with AGC that progressed during 1 or more previous chemotherapy regimens were randomized to a standard dose of weekly paclitaxel (80 mg/m2, standard dose arm) or an escalated dose of weekly paclitaxel (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2on day 15 unless severe toxicity nor neutropenia<1500 is observed, escalated dose arm). The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and safety Results: From September 2010 to November 2011, a total of 90 patients were randomised. Number of previous line of chemotherapy was 1 in 55% and 2 or more in other 45%. Among the 44 patients of dose escalated arm, the dose of wPTX was escalated to 100 mg/m2 in 41 patients (93.2%) and then to 120 mg/m2in 29 patients (65.9%). Median PFS was significantly longer in dose escalated arm than standard dose (4.3 months. vs. 2.5 months, HR, 0.61; 95% CI, 0.39-0.95; p=0.03). ORR was 30.3% with dose escalation and 17.1% with standard dose (p=0.2). DCR was significantly higher with dose escalation (78.8% vs. 48.6%, p=0.009). Frequency of neutropenia (grade 1-4) was significantly higher with dose escalation (88.7% vs. 60.0%, p=0.002), but no significant difference was observed in grade 3/4 (40.9% vs.31.1%, p=0.34). Grade 3 peripheral sensory neuropathy was relatively common in dose escalated arm (13.6% vs. 6.7%, p=0.27). Conclusions: Dose escalated wPTX was associated with significantly longer PFS and higher DCR in patients with previously treated AGC in comparison with standard dose. The result of OS will be presented at the meeting Clinical trial information: UMIN000004055.
Efficacy analyses of a randomized phase III clinical trial of combined therapy with CPT-11/CDDP versus CPT-11 alone in patients with advanced or recurrent gastric cancer refractory to prior S-1 chemotherapy.
Authors: Inagaki Hitoshi , Nishikawa Kazuhiro , Fujitani Kazumasa , Sugimoto Naotoshi , Shigematsu Tadashi , Ishiguro Tohru , Tsuburaya Akira , Nakamura Masato , Nashimoto Atsushi , Yamane Takao , Yamada Makoto , Imano Motohiro , Iijima Shohei , Oka Yoshio , Kataoka Masato , Hironaka Shuichi , Andoh Hideaki , Morita Satoshi , Sakamoto Junichi , Tsujinaka Toshimasa
Published: February 2017

69

Background: There has been no established regimen as the second-line treatment for advanced gastric cancer (AGC), though CPT-11 showed survival benefit over BSC. Combination of CPT-11 with CDDP is one of the promising regimens as the second-line chemotherapy after S-1 mono-therapy. Methods: This is a prospective, multicenter randomized phase III study comparing CPT-11+CDDP (Arm A) vs. CPT-11 alone (Arm B) in patients with advanced or recurrent gastric cancer resistant to S-1 mono-therapy or prior adjuvant chemotherapy using S-1. Eligibility criteria include histologically confirmed gastric adenocarcinoma, age over 20 years old, PS: 0-2, adequate organ functions and written informed consent. Arm A: patients received CPT 11 60mg/m2 and CDDP 30mg/m2 on day 1, q2w. Arm B: patients received CPT-11 150mg/m2on day 1, q2w. Stratification was made according to PS, advanced or recurrence cases, institution and presence or absence of measurable target lesions. Primary endpoint was overall survival (OS), secondary endpoints were progression free survival (PFS), time to treatment failure (TTF), response rate (RR), and safety. Results: 168 patients were registered between 2007 and 2011. Arm A (n=84) and Arm B (n=84) were well balanced for baseline factors. Median age was 67 vs 68 years old, number of advanced/recurrence after resection was 36/48 vs 35/49, and median number of treatment course was 5 vs. 6 (range:0-31, 0-39). Common grade 3/4 toxicities in Arm A vs. Arm B were neutropenia; 35.4% vs. 27.2% (p=0.259), anemia; 15.9% vs. 3.7% (p=0.009), diarrhea; 0% vs. 2.5% (p=0.152), nausea; 3.7% vs. 4.9% (p=0.687), vomiting; 1.2% vs. 3.7% (p=0.305), anorexia 6.1% vs. 8.6% (p=0.534). The rate of patients who were required dose modification for these toxicities was 22.9% vs 21.4%. The pooled OS, PFS and RR for both Arms were as follows; 13.8 months (95% CI, 10.7 to 17.5), 4.5 months (95% CI, 3.7 to 5.1), and 13.7%. Conclusions: There was no significantly difference in the incidence and severity of adverse events in both Arms except for anemia. Updated efficacy data of secondary endpoints will be presented. Clinical trial information: UMIN000002571.
Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT).
Authors: Von Hoff Daniel D. , Ervin Thomas J. , Arena Francis P. , Chiorean E. Gabriela , Infante Jeffrey R. , Moore Malcolm J. , Seay Thomas E. , Tjulandin Sergei , Ma Wen Wee , Saleh Mansoor N. , Harris Marion , Reni Michele , Ramanathan Ramesh K. , Tabernero Josep , Hidalgo Manuel , Van Cutsem Eric , Goldstein David , Wei Xinyu , Iglesias Jose Luis , Renschler Markus Frederic
Published: February 2017

LBA148

Background: nab-Paclitaxel (nab-P, 130 nm albumin-bound paclitaxel) provides tumor selective localization via transcytosis across the endothelium, potential tumor uptake via macropinocytosis, and improved pharmacokinetics vs cremophor-paclitaxel. In vitro, nab-P increased tumoral gemcitabine (G) levels, and in a phase I/II study in metastatic pancreatic cancer (mPC) nab-P + G showed promising activity. Methods: Patients (pts) with mPC were randomized to nab-P 125 mg/m2, followed by G 1000 mg/m2 on days 1, 8, and 15 every 4 weeks or G 1000 mg/m2 weekly for 7 weeks (cycle 1), then on days 1, 8, and 15 every 4 weeks (≥ cycle 2). For the primary endpoint of overall survival (OS), 608 events from 842 patients provided a power of 0.9 to detect a HR of 0.769 (2-side α = 0.049). Results: 861 pts received therapy. Baseline pt characteristics were well balanced. Median age was 63 years, Karnofsky performance status was 90-100 in 60% and ≤80 in 40% of pts, 43% had head of pancreas lesions, 84% had liver and 39% had lung metastases, and 52% of pts had CA19-9 ≥59 x ULN. Treatment duration was 4 vs 3 months in nab-P + G vs G. The relative protocol G dose was 75% vs 85% in nab-P + G vs G; nab-P dose was 81%. OS, progression-free survival (PFS), time to treatment failure (TTF), and overall response rate (ORR) were significantly improved in the nab-P + G arm (Table). Most common grade ≥3 AEs were neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%) in the nab-P + G vs G arms. Grade ≥3 neuropathy improved to grade ≤1 in 29 days. Febrile neutropenia was reported in 3% (nab-P + G) vs 1% (G) pts. Conclusions: In this multinational, multiinstitutional study, nab-P + G was well tolerated and superior to G with statistically significant and clinically meaningful results in all endpoints and across subgroups. Clinical trial information: NCT00844649. [Table: see text]
Preliminary results of a prospective study of 18F-NAF PET/CT in prostate cancer.
Authors: Park Jong Chul , Kurdziel Karen A. , Lindenberg Liza , Gulley James L. , Madan Ravi Amrit , Wood Lauren V. , McKinney Yolanda , Choyke Peter L. , Dahut William L. , Apolo Andrea Borghese
Published: February 2017

103

Background: We performed a prospective study of 18F-NaF PET/CT bone scan (NaF) in the detection of bone metastases in men with prostate cancer. We previously reported that NaF identified more malignant lesions than Technetium-99m MDP bone scan (TcBS) (ASCO 2012 10589). This study evaluates the ability of NaF to detect bone metastasis in men with normal TcBS and also explores the change in NaF over 6 and 12 months compared to PSA changes. Methods: In a prospective 2-arm study, 60 men with prostate cancer (30 with and 30 without bone metastases by TcBS) were studied (ages 51-79). All had NaF and TcBS at baseline, followed by repeat NaF at 6 and 12 months. TcBS and NaF were reviewed by experienced nuclear medicine physicians. Abnormal foci of uptake on TcBS and NaF were classified as benign, malignant or indeterminate. Malignant uptake on NaF was confirmed by characteristic osteoblastic features on CT. Scan results were categorized as “positive” if any malignant lesion was present. In the 6 and 12 months follow up NaF, results were categorized as progression of disease (PD) = any new lesions or SUV increase > 30% in known lesions; stable disease (SD) = no new lesions or SUV changes < 30% in known lesions; and improvement of disease (ID) = resolution of known lesions or decrease SUV > 30% in known lesions. Results: 60 men have enrolled on study, 58 and 34 completed 6 and 12 month follow-up respectively. At baseline, 14 of 30 (47%) men with negative TcBS showed evidence of bone metastases in NaF (PSA mean 45); 7/14 had 2 baseline NaF and showed positive results in both, demonstrating reproducibility; 13/14 and 7/14 had follow up NaF at 6 and 12 months, respectively, all of which remained positive. In follow-up, 13/58 men at 6 months and 8/34 men at 12 months had PD from baseline on NaF, of whom 5/13 (38%) at 6 months and 5/8 (63%) at 12 months also had a PSA increase > 50%. All men who had PD on NaF at 6 months and had a follow-up scan at 12 months remained positive. 15 men at 6 months and 7 men at 12 months had ID on follow-up NaF, of which 11/15 (73%) and 6/7 (86%) had PSA decrease > 50% at 6 and 12 months, respectively. Conclusions: Early results of this ongoing NaF study are encouraging and suggest NaF identifies metastatic bone disease earlier than TcBS and correlates with changes in PSA. Clinical trial information: NCT01240551.
Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.
Authors: Tombal Bertrand , Borre Michael , Rathenborg Per , Werbrouck Patrick , Heidenreich Axel , Iversen Peter , Baskin-Bey Edwina S. , Perabo Frank , Phung De , Smith Matthew Raymond
Published: February 2017

18

Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor–binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (>80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability. Results: Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (>80% PSA decline at wk 25) was 93%, with a median (range) decrease of −99% (−100, −57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (−32, 300) and 58% (−49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related. Conclusions: ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT01302041.
Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer.
Authors: Sella Avishay , Sella Tal , Peer Avivit , Berger Raanan , Frank Stephen Jay , Gez Eli , Sharid David , Hayat Henry , Hanovich Ekaterina , Kovel Svetlana , Rosenbaum Eli , Neiman Victoria , Keizman Daniel
Published: February 2017

186

Background: Cabazitaxel (CAB) and abiraterone-acetate (AA) have been approved after docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following docetaxel and AA in CRPC. Methods: Over 13 months until December 2011, 130 CRPC patients received AA after docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). Results: Fourteen (58.3%) received CAB/prednisone at 20 mg/m2 and 10 patients 25 mg/m2, overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. Conclusions: Limited number of patients with CRPC received CAB following docetaxel and AA. In this selected population CAB was active. Response to prior docetaxel was associated with prolonged survival to CAB therapy.
Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.
Authors: Nilsson Sten , Sartor A. Oliver , Bruland Oyvind S. , Fang Fang , Aksnes Anne-Kirsti , Parker Chris
Published: February 2017

19

Background: Bone metastases (mets), present in >90% of patients (pts) with CRPC, may cause severe pain. In a phase II dose-response study with Ra-223 treatment, pain response (pain reduction and stable analgesic consumption) was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase III ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n=614; placebo, n=307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR=0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The hazard ratios for time to initial opioid use and time to external beam radiation therapy (EBRT) were analyzed using the Cox proportional hazards model. Pts with no opioid use at baseline were included in the pain analyses. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer in the Ra-223 group vs placebo (HR=0.670, 95% CI: 0.525-0.854). Fewer Ra-223 pts reported bone pain as an AE compared to placebo pts (50% vs 62%). 269 pts in the Ra-223 group and 139 pts in the placebo group had no opioid use at baseline. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38% compared to placebo (HR=0.621, 95% CI: 0.456-0.846). Fewer pts in the Ra-223 group (36%) than in the placebo group (50%) required opioid use for pain relief. Conclusions: These ALSYMPCA results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in patients with CRPC and bone metastases. Clinical trial information: NCT00699751.
Certificate of need and use of IMRT in elderly patients with low-risk prostate cancer.
Authors: Lu-Yao Grace L. , Nelson Carl , Shen Shunhua , Shao Yu-Hsuan , Li Hui , Mayer Tina M. , Moore Dirk , Kim Sung
Published: February 2017

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Background: Certificate of Need (CON) laws are optional from state to state, and are meant to limit proliferation of certain unnecessary medical facilities. Theoretically, CON should limit the use of IMRT (intensity modulated radiation therapy) in the population who likely would benefit from it the least: older or debilitated men with low risk prostate cancer. We evaluated the effect of CON on IMRT use in these patients in a population-based cohort. Methods: Using the Surveillance, Epidemiology and End Results (SEER) database linked with Medicare files, we identified male residents of SEER regions who were diagnosed between 2004-07 with low- risk prostate cancer (T1, Gleason≤6, PSA<10) and were either ≥70 years old or ≥65 years old with Charlson comorbidity score ≥ 2. The endpoint was percentage of newly diagnosed patients who were treated with IMRT within 12 month of cancer diagnosis. Logistic regression was used to assess the impact of CON laws on IMRT use. Results: 2,263 (33%) of the patients came from states with radiation oncology CON laws, whereas 4,622 (67%) came from non-CON states. IMRT was performed on 28% of CON patients versus 24% of non-CON patients. Logistic regression analysis using two sided p-values revealed that IMRT is actually utilized more often in CON states than in non-CON states, with an odds ratio of 1.23 (95% CI 1.10-1.39, p<0.001). Conclusions: CON laws do not effectively limit use of IMRT in older or debilitated patients with low risk prostate cancer.
Who dies from prostate cancer in a Western country? A multicenter analysis.
Authors: Loriot Yohann , Eymard Jean-Christophe , Albiges Laurence , Massard Christophe , Patrikidou Anna , Ileana Ecaterina , Di Palma Mario , Bossi Alberto , Blanchard Pierre , Escudier Bernard , Fizazi Karim
Published: February 2017

211

Background: In the last 30 years, a major shift in initial staging has occurred for men with prostate cancer (CaP) in many Western countries, with the incidence of detectable metastases at diagnosis decreasing from more than half the cases in the 1970s to currently less than 10%. Still, prostate cancer is the second killing neoplasm in men. We used two prospective databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of metastatic CRPC in the modern era. Methods: The outcome of 190 men with CaP treated for metastatic disease from 2007-2011 was studied. Characteristics of patients who died from CaP were analyzed. Results: After a median follow-up of 6.8 years, 112 patients had died from CaP and 109 were assessable for presence of metastasis at initial diagnosis. Of these 109 pts, 53 (49%) had detectable metastasis at diagnosis: 43 pts (81%), 6 pts (11%) and 17 pts (32%) had bone, visceral; and lymph nodes metastases, respectively. Overall, 10 pts (19%) had more than one metastatic site. Median time to CRPC was 16 months (range: 3-122 months) and median overall survival was 5 years (CI 95%: 4.6 – 6.6 years) for these pts with detectable metastasis at diagnosis. Among patients with localized CaP at diagnosis (n=56; 51%), 23 pts (41%) had T stage ≥ 3, 23 pts (41%) had a Gleason score ≥ 8. Their median PSA was 15 ng/ml (4-400). Overall, 39 pts (70%) were classified as having a high-risk CaP. 13 patients (23%) dying from CaP had an initial Gleason score ≤ 6. The median overall survival was 7 years (CI 95%: 6.1 – 9.1 years). Conclusions: In the modern era, approximately half of the patients eventually dying from CaP had detectable metastases at diagnosis. The paradigm of patients progressing from localized disease to metastatic disease and eventually death is represented only in the other half. Further efforts should be made to conduct clinical trials in patients with newly diagnosed metastatic prostate cancer.
Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3.
Authors: Milowsky Matthew I. , Dittrich Christian , Duran Martinez Ignacio , Jagdev Satinder , Millard Frederick E. , Sweeney Christopher , Bajorin Dean F. , Cerbone Linda , Dunn Robert M. , Sen Paramita , Shi Michael , Kay Andrea C. M. , Squires Matthew , Sternberg Cora N.
Published: February 2017

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Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression. Methods: Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simon’s 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if ≥ 2 responses seen in stage 1). Results: A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in ≥ 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups. Conclusions: Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment. Clinical trial information: NCT00790426.