747 Background: In the RAS wt population of APEC, q2w cetuximab combined with 1L FOLFOX or FOLFIRI achieved a best confirmed overall response rate (BORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior 1L pivotal studies involving weekly (qw) cetuximab. In this hypothesis-generating subgroup analysis, we evaluated the impact of TS in APEC study patients with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with BORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI; subsequent analyses considered patients who were RAS wt ( KRAS/ NRAS, exons 2-4). TS was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for TS; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the TS subgroups reflected the known differences between L- and R-sided mCRC. Efficacy data for the TS subgroups are summarized in the table. Conclusions: Consistent with prior 1L pivotal studies involving qw cetuximab, a prognostic effect of TS in patients receiving 1L q2w cetuximab was confirmed in APEC. BORR remained ≥50% in patients with R-sided mCRC, in line with prior evidence that use of cetuximab may be appropriate when tumor shrinkage/cytoreduction is the goal. These hypothesis-generating data also raise the possibility of synergy between cetuximab and, in particular, irinotecan for PFS and OS in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. [Table: see text]

3534 Background: In the RAS wt population of APEC, q2w cetuximab combined with first-line FOLFOX or FOLFIRI achieved an overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior first-line pivotal studies involving weekly cetuximab. In this subgroup analysis, we evaluated the impact of tumor side in the APEC study population with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with ORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI. Tumor side was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for tumor side; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the tumor side subgroups reflected the known differences between L- and R-sided mCRC; indeed, 95.4% and 75.9% of patients had BRAF wt disease, respectively. Efficacy data are summarized in the Table. Conclusions: Consistent with prior first-line pivotal studies with weekly cetuximab, a prognostic effect of tumor side in patients receiving first-line q2w cetuximab was confirmed in APEC. In patients with R-sided mCRC, ORR remained ≥ 50%, and resection rate was comparable to that of L-sided patients, in line with prior evidence showing that use of cetuximab may be appropriate when rapid tumor shrinkage is the goal. These hypothesis-generating data raise the possibility of a synergy between cetuximab and irinotecan in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. L-side R-side Cetuximab + FOLFIRI Cetuximab + FOLFOX Total Cetuximab + FOLFIRI Cetuximab + FOLFOX Total n 43 87 130 10 19 29 ORR, % 74.4 65.5 68.5 50.0 52.6 51.7 Median PFS, months 12.8 14.2 14.0 15.4 8.3 8.9 Median OS, months 31.7 30.6 30.6 32.1 21.8 24.6 Resection rate, % 2.3 14.9 10.8 10.0 10.5 10.3

Introduction: Conventional response parameters (eg, RECIST-defined objective response rate and progression-free survival [PFS]) do not fully recapitulate – either qualitatively or quantitatively – the true impact of targeted therapies on overall survival (OS) in mCRC; thus, novel metrics are required. In patients with RAS-wt mCRC, DpR – one such innovative response metric – has been shown to be induced effectively by first-line chemotherapy plus weekly cetuximab in the CRYSTAL, OPUS, and FIRE-3 studies. The present analysis evaluated the association between DpR and PFS and OS in the RAS-wt population from the Asia-Pacific, multicenter, nonrandomized, phase 2 APEC study.Methods: APEC enrolled 289 patients with KRAS-wt mCRC. Eligible patients received cetuximab once every 2 weeks plus investigator's choice of FOLFOX or FOLFIRI. Study treatment (either all drugs together or maintenance cetuximab in case of early withdrawal of chemotherapy) continued until disease progression, dose-limiting toxicity, or consent withdrawal. RAS status was assessed retrospectively by ion torrent next-generation sequencing on evaluable samples. DpR was defined as the extent of maximal tumor shrinkage (the sum of tumor diameters at the nadir divided by the sum of tumor diameters at baseline) and was expressed as a percentage.Results: Median PFS and OS in the RAS-wt population (n = 167) of APEC were 13.0 and 28.4 months, respectively; the best confirmed objective response rate was 64.7%, and 10.8% of patients underwent curative R0 resections. This study was not designed to formally assess efficacy differences between treatment subgroups; nevertheless, no major differences between patients receiving FOLFOX vs FOLFIRI were detected. There were no unexpected safety findings. The extent of tumor shrinkage was similar between the FOLFOX and FOLFIRI treatment subgroups; among patients whose disease did not progress, tumor size continued to decrease as the duration of treatment increased. 159 patients with RAS-wt mCRC were evaluable for DpR: median DpR was 62.2% (interquartile range [IQR], 39.1%–80.0%) in the overall DpR-evaluable population; in the FOLFOX plus cetuximab (n = 103) and FOLFIRI plus cetuximab (n = 56) treatment subgroups, median DpR was 62.2% (IQR, 40.0%–80.7%) and 62.5% (IQR, 38.1%–79.0%), respectively. The median time to tumor size nadir was 5.9 months (95% CI, 5.6–7.6 months) in the overall DpR-evaluable population; median time to nadir was 5.9 months (95% CI, 5.6–7.6 months) and 7.4 months (95% CI, 5.1–9.2 months) in the FOLFOX and FOLFIRI treatment subgroups, respectively. Notably, there appeared to be an association between the extent of DpR and time to nadir: patients experiencing a deeper response seemed to achieve maximal tumor shrinkage later than patients with a less deep response. Furthermore, the data suggest that there was a relationship between the extent of DpR and PFS/OS (Figure).Conclusion: These findings – obtained using a once-every-2-weeks dosing regimen – compare favorably to earlier subgroup analyses of analogous pivotal studies involving chemotherapy plus weekly cetuximab. DpR seems to be a sensitive indicator of response and is likely to be associated with PFS and OS. The phase 2 APEC study further suggests that patients with RAS-wt mCRC may benefit from an increased duration of treatment with FOLFOX or FOLFIRI plus cetuximab. Introduction: Conventional response parameters (eg, RECIST-defined objective response rate and progression-free survival [PFS]) do not fully recapitulate – either qualitatively or quantitatively – the true impact of targeted therapies on overall survival (OS) in mCRC; thus, novel metrics are required. In patients with RAS-wt mCRC, DpR – one such innovative response metric – has been shown to be induced effectively by first-line chemotherapy plus weekly cetuximab in the CRYSTAL, OPUS, and FIRE-3 studies. The present analysis evaluated the association between DpR and PFS and OS in the RAS-wt population from the Asia-Pacific, multicenter, nonrandomized, phase 2 APEC study. Methods: APEC enrolled 289 patients with KRAS-wt mCRC. Eligible patients received cetuximab once every 2 weeks plus investigator's choice of FOLFOX or FOLFIRI. Study treatment (either all drugs together or maintenance cetuximab in case of early withdrawal of chemotherapy) continued until disease progression, dose-limiting toxicity, or consent withdrawal. RAS status was assessed retrospectively by ion torrent next-generation sequencing on evaluable samples. DpR was defined as the extent of maximal tumor shrinkage (the sum of tumor diameters at the nadir divided by the sum of tumor diameters at baseline) and was expressed as a percentage. Results: Median PFS and OS in the RAS-wt population (n = 167) of APEC were 13.0 and 28.4 months, respectively; the best confirmed objective response rate was 64.7%, and 10.8% of patients underwent curative R0 resections. This study was not designed to formally assess efficacy differences between treatment subgroups; nevertheless, no major differences between patients receiving FOLFOX vs FOLFIRI were detected. There were no unexpected safety findings. The extent of tumor shrinkage was similar between the FOLFOX and FOLFIRI treatment subgroups; among patients whose disease did not progress, tumor size continued to decrease as the duration of treatment increased. 159 patients with RAS-wt mCRC were evaluable for DpR: median DpR was 62.2% (interquartile range [IQR], 39.1%–80.0%) in the overall DpR-evaluable population; in the FOLFOX plus cetuximab (n = 103) and FOLFIRI plus cetuximab (n = 56) treatment subgroups, median DpR was 62.2% (IQR, 40.0%–80.7%) and 62.5% (IQR, 38.1%–79.0%), respectively. The median time to tumor size nadir was 5.9 months (95% CI, 5.6–7.6 months) in the overall DpR-evaluable population; median time to nadir was 5.9 months (95% CI, 5.6–7.6 months) and 7.4 months (95% CI, 5.1–9.2 months) in the FOLFOX and FOLFIRI treatment subgroups, respectively. Notably, there appeared to be an association between the extent of DpR and time to nadir: patients experiencing a deeper response seemed to achieve maximal tumor shrinkage later than patients with a less deep response. Furthermore, the data suggest that there was a relationship between the extent of DpR and PFS/OS (Figure). Conclusion: These findings – obtained using a once-every-2-weeks dosing regimen – compare favorably to earlier subgroup analyses of analogous pivotal studies involving chemotherapy plus weekly cetuximab. DpR seems to be a sensitive indicator of response and is likely to be associated with PFS and OS. The phase 2 APEC study further suggests that patients with RAS-wt mCRC may benefit from an increased duration of treatment with FOLFOX or FOLFIRI plus cetuximab.

566 Background: The Asia-Pacific, multicenter, nonrandomized, phase II APEC study previously reported that first-line therapy for pts with KRAS ex 2 wt mCRC consisting of C once every 2 weeks combined with FOLFOX or FOLFIRI achieved efficacy and safety profiles comparable to those reported in analogous pivotal studies involving weekly C. This final analysis presents OS data from the KRAS wt intent-to-treat (ITT) population, as well as subgroup efficacy analyses stratified by BRAF, PIKC3A, and all RAS mutation status. Methods: Eligible pts received C once every 2 weeks (day 1 of each cycle, 500 mg/m2) with FOLFOX or FOLFIRI (investigator’s choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. The primary endpoint was best confirmed overall response as assessed by RECIST 1.0; progression-free survival (PFS) and OS were secondary endpoints. In the evaluable populations, the status of BRAF, PIK3CA, and all RAS mutations was assessed retrospectively by pyrosequencing. Results: 42 months after the last patient was enrolled, median OS in the KRAS wt population was 26.8 months (Table). There were no unexpected safety findings. Additional biomarker results—including objective response rate (ORR), PFS, and OS subgroup analyses stratified on BRAF, PIKC3A, and all RAS mutation status—will be presented. Conclusions: The observed median OS of 26.8 months in the KRAS wt population is comparable to that reported in prior pivotal studies involving weekly C plus FOLFOX or FOLFIRI in the first line. These results suggest that C plus FOLFOX or FOLFIRI in a once-every-2-weeks regimen is active and tolerable as first-line therapy in this Asia-Pacific study population and a convenient alternative to weekly administration. Clinical trial information: NCT00778830. [Table: see text]

PD0028). This subgroup analysis of the APEC study investigated tumor response and progression-free survival (PFS) according to treatment in patients grouped by tumor EGFR expression status. Methods: Eligible patients received cetuximab administered every 2 weeks (day 1 of each cycle, 500 mg/m) with, based on investigator’s choice, either FOLFOX or FOLFIRI. Study treatment was continued until disease progression, the occurrence of unacceptable toxicity or withdrawal of consent. The primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks, PFS was a secondary endpoint. EGFR expression was determined retrospectively by immunohistochemistry (IHC) using the Dako EGFR pharmDx kit with a cutoff point of ≥5% of tumor cells exhibiting a staining intensity of at least 1+. Best overall objective response and PFS were determined according to treatment in patients grouped by whether tumors were EGFR detectable or EGFR undetectable. Results: Of the 289 patients in the intent to treat (ITT) population of the APEC study, tumor samples from 154 (53%) patients were available for EGFR IHC analysis, with the majority subsequently evaluable for EGFR expression status (147/154 [95%]). EGFR expression was detectable in 120 tumors (82%) and was undetectable in 27 tumors (18%) from the 147 evaluable patients. There were markedly more Caucasian (22/120 [18%] vs 0/27) and fewer Asian patients (97/120 [81%] vs 27/27 [100%]) in the EGFR detectable compared with the EGFR undetectable groups. Other baseline characteristics in these groups were comparable. Objective response rates (ORR, 58.8% vs 55.8%) and median PFS times (11.1 vs 11.1 months) were similar in the ITT compared with the EGFR evaluable populations, and also in the FOLFOX + cetuximab and FOLFIRI + cetuximab treatment groups in these populations (Table). In patients treated with FOLFOX + cetuximab, the ORR was 60.3% (47/78 patients) in the EGFR detectable group and 50.0% (8/16 patients) in the EGFR undetectable group. In patients treated with FOLFIRI + cetuximab, the ORR was 54.8% (23/42 patients) in the EGFR detectable group and 36.4% (4/11 patients) in the EGFR undetectable group. Median PFS times were generally comparable according to treatment in the EGFR detectable and EGFR undetectable groups (Table). Conclusion: In this retrospective subgroup analysis of APEC study patients, there were no major differences in ORRs and median PFS times between the subgroups of patients with EGFR detectable and EGFR undetectable tumors. Because of the small numbers of patients in some subgroups, no definite conclusions could be made with regard to EGFR expression as a clinically useful biomarker for the activity of chemotherapy plus cetuximab. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. po st er di sc us si on s poster discussions Annals of Oncology 25 (Supplement 2): ii5–ii13, 2014 doi:10.1093/annonc/mdu164.1 Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_2/ii5/155740 by guest on 10 August 2018

Introduction: The Asia-Pacific, multicenter, non-randomized APEC study previously reported that the efficacy and safety profiles of cetuximab every 2 weeks combined with first-line FOLFOX or FOLFIRI in patients with KRAS wild-type metastatic colorectal cancer (mCRC) were similar to those reported in pivotal studies for either chemotherapy regimen plus weekly cetuximab (Cheng et al Ann Oncol 2013:24(S4);Abstract PD0028). This subgroup analysis of the APEC study investigated tumor response and progression-free survival (PFS) according to treatment in patients grouped by tumor EGFR expression status. Methods: Eligible patients received cetuximab administered every 2 weeks (day 1 of each cycle, 500 mg/m2) with, based on investigator's choice, either FOLFOX or FOLFIRI. Study treatment was continued until disease progression, the occurrence of unacceptable toxicity or withdrawal of consent. The primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks, PFS was a secondary endpoint. EGFR expression was determined retrospectively by immunohistochemistry (IHC) using the Dako EGFR pharmDxtrade kit with a cutoff point of ≥5% of tumor cells exhibiting a staining intensity of at least 1+. Best overall objective response and PFS were determined according to treatment in patients grouped by whether tumors were EGFR detectable or EGFR undetectable. Results: Of the 289 patients in the intent to treat (ITT) population of the APEC study, tumor samples from 154 (53%) patients were available for EGFR IHC analysis, with the majority subsequently evaluable for EGFR expression status (147/154 [95%]). EGFR expression was detectable in 120 tumors (82%) and was undetectable in 27 tumors (18%) from the 147 evaluable patients. There were markedly more Caucasian (22/120 [18%] vs 0/27) and fewer Asian patients (97/120 [81%] vs 27/27 [100%]) in the EGFR detectable compared with the EGFR undetectable groups. Other baseline characteristics in these groups were comparable. Objective response rates (ORR, 58.8% vs 55.8%) and median PFS times (11.1 vs 11.1 months) were similar in the ITT compared with the EGFR evaluable populations, and also in the FOLFOX + cetuximab and FOLFIRI + cetuximab treatment groups in these populations (Table). In patients treated with FOLFOX + cetuximab, the ORR was 60.3% (47/78 patients) in the EGFR detectable group and 50.0% (8/16 patients) in the EGFR undetectable group. In patients treated with FOLFIRI + cetuximab, the ORR was 54.8% (23/42 patients) in the EGFR detectable group and 36.4% (4/11 patients) in the EGFR undetectable group. Median PFS times were generally comparable according to treatment in the EGFR detectable and EGFR undetectable groups (Table). Conclusion: In this retrospective subgroup analysis of APEC study patients, there were no major differences in ORRs and median PFS times between the subgroups of patients with EGFR detectable and EGFR undetectable tumors. Because of the small numbers of patients in some subgroups, no definite conclusions could be made with regard to EGFR expression as a clinically useful biomarker for the activity of chemotherapy plus cetuximab.

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.

e14501 Background: Randomized studies have shown that weekly cetuximab added to first-line FOLFOX or FOLFIRI improves clinical outcome in patients (pts) with KRAS wild-type (wt) mCRC. This Asia-Pacific multicenter study investigated FOLFOX or FOLFIRI + every 2 weeks cetuximab (C) as first-line therapy in pts with KRAS wt mCRC. Methods: Eligible pts received every 2 weeks cetuximab (d1 500 mg/m2 q14d) with, based on investigator’s choice, either FOLFOX (oxaliplatin 100 mg/m2, folinic acid [FA] 200 mg/m2 L-form or 400 mg/m2 racemic, then 5-fluorouracil [5-FU], as a 400 mg/m2 iv bolus and a 2400 mg/m2 infusion over 46 h) or FOLFIRI (irinotecan 180 mg/m2, FA 200 mg/m2 L-form, or 400 mg/m2 racemic, then 5-FU, as a 400 mg/m2 iv bolus and a 2400 mg/m2infusion over 46 h), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks. Results: Data cut-off was 86 weeks after the date of last patient included. The ITT/safety population comprised 289 pts; 65.1% received FOLFOX + C and 34.9% FOLFIRI + C. Baseline characteristics were generally well balanced. Leukocyte count >10000/mm3was more frequent (16.5% vs 7.9%) and prior adjuvant treatment less frequent (21.3% vs 46.5%) in pts receiving FOLFOX + C. Response (CR or PR) was observed in 170 (58.8%) pts. The overall R0 resection rate was 10.0%. Survival data are not mature. Cetuximab dose intensity was >80% in 77.7% (FOLFOX + C) and 74.3% (FOLFIRI + C) of pts. Most frequent grade 3/4 adverse events (>10% in either arm) were neutropenia, diarrhea, hypokalemia, neuropathy (FOLFOX + C only) and skin reactions. Conclusions: Efficacy and safety profiles of every 2 weeks cetuximab combined with FOLFOX or FOLFIRI were similar to those reported for either chemotherapy plus weekly cetuximab in pivotal studies. Clinical trial information: NCT00778830. [Table: see text]

259 Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC. Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks. Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%). Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.

89 Background: Perioperative chemotherapy has been shown to improve outcomes among patients with locally advanced gastric adenocarcinoma. As docetaxel (D), cisplatin (C), and capecitabine (X) are active agents in gastric adenocarcinoma, we conducted a phase II trial to assess the efficacy and tolerability of preoperative DCX in patients with gastric adenocarcinoma. Methods: We enrolled patients with locally advanced gastric adenocarcinoma (clinical T3/4 or N positive) to preoperative DCX repeated every 21 days for three cycles, followed by surgery. The first cohort of 10 patients received docetaxel 35 mg/m2, cisplatin 35mg/m2 on days 1 and 8, with capecitabine 750 mg/m2 twice daily from day 1 to day 14. A subsequent cohort of another 11 patients had dose modifications for docetaxel and cisplatin, both to 30mg/ m2 on days 1 and 8. Results: Twenty-one patients were recruited. Median age was 61 years. Seventy-one percent of patients completed a total of 3 cycles of planned chemotherapy. Fourteen patients have successfully undergone surgery. R0 resection rate was 88%. Pathological complete response (pCR) and near complete response (pnCR) were both 17%. Preoperative radiological assessment showed a partial response rate of 65% after 2 cycles of treatment. Good pathological response (pCR and pnCR) was associated with better event-free survival (26 months vs 12 months, p=0.031). Common grade 3/4 toxicities were diarrhea (38%), neutropenia (30%), stomatitis (14%) and hypokalemia (14%). However, the diarrhea rate was reduced to 15% with dose modifications as mentioned above after 50% of the first cohort of 10 patients developed grade 3/4 diarrhea during the first cycle of chemotherapy. Febrile neutropenia rate was 14%. There was one treatment related death before surgery but no postoperative mortality. Conclusions: Preoperative DCX is highly active with modest toxicity in locally advanced gastric adenocarcinoma. DCX represents an attractive alternative regimen without the need for protracted infusional drug in perioperative chemotherapy for patients with locally advanced gastric adenocarcinoma. Good pathological response is associated with better outcome.

Effects of CYP4F2 and GGCX genetic variants on maintenance warfarin dose in a multi-ethnic Asian population -

BACKGROUND:The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.PATIENTS AND METHODS:Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs).RESULTS:Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose.CONCLUSIONS:SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.

Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer.

4068 Background: KRAS oncogene mutation status is predictive of efficacy of cetuximab alone or combined with chemotherapy (CT) in mCRC. Previous data from the phase III CRYSTAL trial showed that adding cetuximab to FOLFIRI in first-line mCRC significantly improved the overall response rate (ORR) and progression-free survival (PFS) in pts with KRAS wild-type (wt) tumors. The serine-threonine kinase BRAF is a direct downstream effector of KRAS. Here, we report the influence of KRAS and BRAF status on mature overall survival (OS) data. Methods: DNA was extracted from archived tumor material where available from randomized pts. KRAS and BRAF mutation status (wt or mutant [mt]) was determined by quantitative PCR. Treatment arms were compared using two-sided log-rank tests (5% significance level) for PFS and OS, and the CMH test for best ORR. Results: The KRAS-evaluable cohort (n=540; 64.4% KRAS wt) was similar to the overall ITT group. In KRAS wt pts, adding cetuximab to FOLFIRI significantly increased the odds for tumor response nearly 2-fold, reduced the risk of progression by 32% and extended median OS from 21.0 months (mo) to 24.9 mo (details in Table ). KRAS mt pts did not benefit from cetuximab. Data on the impact of BRAF mutations on cetuximab activity will be presented at the meeting. In the FOLFIRI and cetuximab + FOLFIRI arms, 31.2% and 36.1% of pts, respectively, received no further line of therapy, while 25.4% and 6.2%, respectively, received EGFR antibody therapy. Conclusions: The benefits of adding cetuximab to CT were greater in KRAS wt pts than ITT pts for all clinically relevant endpoints. KRAS is a key biomarker for selecting a targeted therapy combined with standard CT in first-line mCRC. [Table: see text] [Table: see text]

4062 Background: The pivotal BOND study (Cunningham et al. N Engl J Med 2004;351:337–45) demonstrated the efficacy of cetuximab alone or in combination with irinotecan in metastatic colorectal cancer (mCRC) after irinotecan failure. As further studies have been performed in heavily pretreated patients who had recently failed irinotecan, this integrated analysis was performed to assess the consistency of cetuximab response across geographic regions. Methods: BOND was an open-label, randomized study conducted in 11 European countries. The single-arm MABEL study assessed cetuximab plus irinotecan in a larger community practice setting in Europe. Smaller versions of this study were conducted in Latin America (LABEL) and Australasia (ELSIE). All patients enrolled in these phase II studies had EGFR-detectable mCRC that had progressed on prior irinotecan therapy. Results: Response rates, disease-control rates, progression-free survival (PFS) time, and overall survival time were similar across the four studies (Table). Conclusions: The addition of cetuximab to irinotecan demonstrated consistent efficacy in studies across Europe, Latin America, and Asia in the second-line treatment of patients with mCRC after irinotecan failure. These results involving over 1,500 patients underline the role of cetuximab and irinotecan as standard treatment for patients after irinotecan failure in the treatment of mCRC. BOND (combination therapy arm) MABEL LABEL ELSIE No. of subjects 218 1147 79 123 Response rate, % (95% CI) 22.9 (17.5–29.1)a 20.1 (17.9–22.6)b 26.6 (17.3–37.7)c 13.8 (8.3–21.2)c Disease-control rate, % (95% CI) 55.5 (48.6–62.2)a 45.2 (42.3–48.2)b 55.7 (44.1–66.9)c 49.6 (40.5–58.8)c Median PFS, weeks (95% CI) 18.0 (12.0–18.9)a 14.1 (13.0–17.1)c 17.4 (11.7–18.9)c 12.1 (9.7–17.7)c PFS rate at 12 weeks, % (95% CI) 56 (3 mo) (48.7–62.6)a 61 (58–64)c 57 (46–68)c 50 (41–59)c Median survival, months (95% CI) 8.6 (7.6–9.6) 9.2 (8.6–9.8) 9.2 (7.9–10.8) 9.5 (7.1–11.7) a WHO criteria –IRC; b Subjective assessment by the investigator; c WHO criteria - Investigator Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck KGaA Merck, Merck KGaA, Merck Serono Merck KGaA Merck KGaA, Merck Serono Merck, Merck Serono

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 ( UGT1A1*60 , g.−3140G>A, UGT1A1*28 and UGT1A1*6 ) and UGT1A9 (g.−118(T) 9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m 2 once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 ( P <0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 ( P >0.05). UGT1A1 – 1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT 10 T/GG6GT 9 C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT 10 T/GG6GT 10 C) diplotype ( P =0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.