Search

4127 Background: In the NAPOLI-1 study, nal-IRI+5-FU/LV significantly increased median OS vs. 5-FU/LV control (6.1 vs. 4.2 mo; unstratified HR = 0.67 [0.49–0.92]; p = .012). This is a subgroup analysis by prior lines of mtx. Methods: Study methodology has been published (Wang-Gillam; Lancet 2016). This exploratory subgroup analysis compares outcomes in pts with 0–1 vs. ≥2 prior mtx lines, based on primary survival analysis data (cut-off February 2014) of the ITT population. Results: OS, PFS and CA19-9 response rates in pts with 0–1 (65.8% of pts) or ≥2 (34.2%) prior mtx lines are shown (see Table). Median OS for nal-IRI+5-FU/LV improved vs. 5-FU/LV by 2.1 mo to 6.2 mo (HR = 0.66; p = .03) in pts with 0–1 prior mtx lines and by 1.1 mo to 5.4 mo (HR = 0.68; p = .18) in pts with ≥2 prior mtx lines. The safety profile was similar between subgroups with nal-IRI+5-FU/LV (≥grade 3 drug-related AEs: 43 [55%] with 0–1 and 20 [51%] with ≥2 prior mtx lines). Conclusions: This post-hoc subgroup analysis shows significant increases for nal-IRI+5-FU/LV over 5-FU/LV in OS, PFS and CA19-9 response in pts with 0–1 prior mtx lines. Median OS benefit was less prominent in later lines, but conclusions are restricted by limited pt numbers. Clinical trial information: NCT01494506. [Table: see text]

e15774 Background: Gemcitabine (GEM) based chemotherapy has been the standard of care for patients with metastatic PDAC with marginal effects on overall survival (OS). In recent years, FOLFIRINOX and Nab-paclitaxel (NAB) + GEM regimens have shown significant survival benefits compared to gemcitabine in clinical trial settings. This study aims to investigate the efficacy of FOLFIRINOX and NAB + GEM versus GEM monotherapy and GEM doublet combinations in real-life settings across different European institutions. Methods: Patients from UK, Sweden, Germany, Italy and Hungary with metastatic PDAC receiving palliative chemotherapy between 2012 and 2015 were included in a retrospective multinational study. Kaplan-Meier method was used for survival analysis. Results: Of the 1089 included patients, 576 (52.9%) were male and 170 (15.6%) underwent primary resection before systemic recurrence. GEM monotherapy was the most commonly used regimen (40.0%; n = 436), followed by combination treatments such as GEM + oxaliplatin, GEM + cisplatin, GEM + capecitabine (24.2%; n = 263), FOLFIRINOX (17,5%; n = 191) and NAB + GEM (7.3%; n = 80). Overall, 6-months and 12-months mortality rate was 48.9% and 72.5%, respectively. The median OS in different groups was: FOLFIRINOX 9.0 months (95% CI 7.1-10.9), NAB + GEM 7.0 months (95% CI 5.8-8.2), other GEM doublet combinations 7.0 months (95% CI 6.0-8.0) and GEM monotherapy 5.0 months (95% CI 4.3-5.7). Compared to GEM monotherapy, intensified chemotherapy either with FOLFIRINOX (p = 0.0001), NAB + GEM (p = 0.02) or GEM doublets (p = 0.0001) was associated with significantly improved survival. Comparison of the different combination regimens was as follows: NAB + GEM vs. FOLFIRINOX (OS: 7.0 vs 9.0 months, p = 0.25), NAB + GEM vs. GEM doublets (OS: 7.0 vs. 7.0 months, p = 0.79) and FOLFIRINOX vs. GEM doublets (OS: 9.0 vs. 7.0 months, p = 0.29). Conclusions: The use of FOLFIRIOX and NAB in clinical routine is variable in Europe. GEM based regimens seem to be the preferred standard of care. Compared to GEM monotherapy, combination treatments improved survival. No significant differences amongst combination therapeutic regimens were identified within our cohort.

4114 Background: Adjuvant chemotherapy following PC resection improves overall survival (OS). It is uncertain whether benefit is influenced by nodal and resection status or other factors. Methods: A systematic review of electronic databases identified published phase 2/3 studies investigating use of adjuvant chemotherapy in pts with resected PC. Efficacy (disease-free survival [DFS], OS, 5 yr OS) was explored using meta-analysis. Subgroup analysis explored effects based on nodal/resection status. Meta-regression also explored influence of age, gender, performance status [PS] and proportion of pts with head of pancreas (HOP) tumors on benefit of adjuvant chemotherapy. Results: Ten studies comprising 3644 pts were included. Two prospective phase 2 studies; 8 phase 3 trials. Median age was 63 yrs (range 24-84), 46% male. In 2268 pts with PS reported; 42% were PS 0, 51% PS 1. Tumor location was reported in 719 pts; 82% had HOP tumors. Of 3524 pts with available data; 33% N- and 67% R0. Overall, in studies of experimental vs control, adjuvant therapy significantly improved DFS (HR 0.67, CI 0.48-0.93, P = 0.02), OS (HR 0.77, 95% CI 0.68-0.87, P < 0.001) and odds of death risk at 5 yrs (OR 0.53, 95% CI 0.41-0.70, P < 0.001). In studies comparing chemotherapy to surgery only, adjuvant therapy also significantly improved DFS (HR 0.57, 95% CI 0.49-0.76, P < 0.001) and OS (HR 0.74, 95% CI 0.64-0.87, P < 0.001). There was a numerical but non-significant greater effect of adjuvant therapy in N- vs N+ pts (HR 0.58 vs 0.71, P for difference = 0.29). There was no difference in effect between pts with R0 or R1 disease (HR 0.70 vs 0.69, P for difference = 0.95). There was greater OS benefit from adjuvant therapy in pts with PS 0 (P = 0.04) and significantly less benefit on 5 yr OS in pts with HOP tumors (P = 0.04). Conclusions: The relative benefit of adjuvant chemotherapy seems similar in N-/N+ and in R0/R1 pts. This will translate into greater absolute benefit in the N+ and R1 pts due to their greater absolute risk of recurrence/death. Adjuvant chemotherapy is recommended for all pts with resected PC, where clinically appropriate, and greater benefit was seen in pts with PS 0 and body/tail tumors.

e15795 Background: Increased NLR and PLR have been associated with poor survival in several malignancies. Here we report the association of NLR and PLR with overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 trial (NCT01494506), which evaluated nal-IRI+5-FU/LV for the treatment of mPDAC patients (pts) after disease progression following gemcitabine-based therapy. Methods: Pts missing baseline NLR/PLR data were excluded. Medians reflect Kaplan-Meier estimates; hazard ratios (HRs) reflect Cox regression analysis. P values in this exploratory analysis are descriptive. Results: Of 116 evaluable pts in the nal-IRI+5-FU/LV arm, 82 (71%) had NLR ≤5 and 44 (38%) had PLR ≤150 (data cutoff: Nov 16, 2015). Of 105 evaluable pts in the 5-FU/LV control arm, 73 (70%) had NLR ≤5 and 36 (34%) had PLR ≤150. In pts with baseline NLR ≤5 or PLR ≤150, median OS and PFS were significantly longer in the nal-IRI+5-FU/LV treatment arm vs the 5-FU/LV control arm (Table). In pts with baseline NLR >5 or PLR >150, median OS and PFS were numerically longer in the treatment vs control arm, but differences were less compelling (95% CIs for HRs included 1). Conclusions: Median OS and PFS were improved with nal-IRI+5-FU/LV vs 5-FU/LV in pts with baseline NLR ≤5 or PLR ≤150. This exploratory analysis extends the prognostic significance of NLR and PLR to the post-gemcitabine setting. Clinical trial information: NCT01494506. [Table: see text]

293 Background: nal-IRI, a liposomal formulation of irinotecan, plus 5-FU/LV is approved in the United States and Taiwan for patients (pts) with mPDAC previously treated with gemcitabine-based therapy. Primary analysis of the NAPOLI-1 trial (NCT01494506) showed that nal-IRI+5-FU/LV significantly improved median overall survival vs 5-FU/LV (6.1 vs 4.2 months; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Herein we report baseline characteristics of pts surviving ≥1 year (data cutoff, Nov 2015). Methods: This analysis includes 117 pts assigned to treatment with nal-IRI 70 mg/m2 (free base) + 5-FU/LV 2400/400 mg/m2 q2w, and 119 pts assigned to treatment with 5-FU/LV 2000/200 mg/m2weekly for weeks 1-4 q6w. Results: A total of 29 (25%) pts in the nal-IRI+5-FU/LV arm and 17 (14%) in the 5-FU/LV arm survived ≥1 year. These pts typically had better performance status, lower CA19-9 (U/mL) levels, and were less likely to have liver metastases at baseline, compared with the overall population (Table). For long-term survivors in the nal-IRI+5-FU/LV arm, a higher proportion of pts had neutrophil-to-lymphocyte ratio (NLR) >5, a marker of poor prognosis, suggesting that higher NLR may potentially be predictive of survival outcome with nal-IRI+5-FU/LV. Conclusions: More pts receiving nal-IRI+5-FU/LV versus 5-FU/LV were alive beyond 1 year. The most prominent prognostic markers of survival ≥1 year included lower CA19-9, KPS ≥90 and absence of liver metastases. These analyses may be limited by small sample sizes. Clinical trial information: NCT01494506. [Table: see text]

303 Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]

Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.

Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4 weeks on/2 weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand–foot syndrome, and hypertension.

Background: HER2 overexpression and/or amplification has been reported as predictive factor to HER2 targeted therapy in breast and gastric cancer, whereas HER3 is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 up-regulation in biliary tract cancers (BTCs).Methods: An electronic search of MEDLINE, ASCO, ESMO and AACR was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridisation (ISH) in BTCs.Results: Out of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5% (95% CI, 18.9% - 34.1%). Studies were classified as “high-quality” (HQ; 27 studies) [IHC overexpression defined as presence of moderate/strong staining] and “low-quality” (11 studies) [“any” expression was considered positive]. When HQ studies were analysed, extra-hepatic BTCs (EH-BTCs) showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma (IHCC) [19.9% (95% CI, 12.8 – 27.1%) vs. 4.8% (95% CI, 0 – 14.5%); p-value 0.0049]. HER2 amplification rate was higher in those patients selected by HER2 overexpression [57.6% (95% CI, 16.2 - 99%)] compared to “unselected” patients [17.9% (95% CI, 0.1 – 35.4%); p-value 0.0072]. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9% (95% CI, 9.7 - 46.1%) and 26.5% (one study), respectively.Conclusions: Up to 20% of EH-BTCs might be HER2 overexpressed, ∼60% of HER2 overexpressed BTCs can be considered amplified while HER3 is overexpressed or amplified in ∼25% of BTCs. These findings may be considered in future trial development.

Intensified chemotherapy for metastatic pancreatic cancer : interim analysis of a large retrospective pan-European database and real life evaluation

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Gastric cancer is the third-leading cause of cancer-related deaths worldwide. Outcomes of current treatment regimens remain unsatisfactory, particularly in pts with advanced gastric cancer. TAK-264 is a novel drug conjugate consisting of a human monoclonal antibody that specifically targets GCC, which is expressed in approximately 70% of gastric cancers, linked to the potent microtubule disrupting agent monomethyl auristatin E. In the first-in-human Phase 1 study ([NCT01577758][1]) evaluating the safety of TAK-264, preliminary signals of clinical activity were reported in pts with gastric, gastroesophageal, and pancreatic carcinoma. The primary objective of this Phase 2 open-label, non-randomized, multicenter study ([NCT02202759][2]) was to evaluate the overall response rate (ORR; complete response + partial response) of adult pts with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction. Here we report the findings from the Interim Analysis (IA). Pts aged ?18 years with histologically-confirmed metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction, who were GCC-positive as demonstrated by immunohistochemistry with an H score ?10 and who had received ?1 prior therapy were eligible for inclusion. TAK-264 1.8 mg/kg was administered as a single 30-minute intravenous infusion on day 1 of a 21-day cycle until disease progression or unacceptable toxicity occurred. Pts were evaluated for a response every 2 cycles. At data cut-off (October 1, 2015), 37 pts had been enrolled (81% male), of which 36 (97%) pts were response-evaluable. The median age at baseline was 63 years (range, 31-81) and the median time from the initial diagnosis was 19.7 months (range, 5-76). Pts had received a median of 3 prior therapies (range, 1-7). Of the 36 pts in the response-evaluable population, the ORR was 6% (2 pts) and stable disease was observed in 15 (42%) pts. Progressive disease was experienced by 19 (53%) pts. All pts received at least one dose of TAK-264 and were included in the safety population. Common adverse events (AEs) observed in ?15% of pts included nausea (49%), fatigue (30%), decreased appetite and asthenia (each 27%), constipation and vomiting (each 22%), peripheral edema (19%), and diarrhea and anemia (each 16%). Diarrhea and neutropenia were the most prevalent Grade ?3 AEs, (each 5%). Other Grade ?3 gastrointestinal AEs included dysphagia, nausea and decreased appetite (each 1%). Results from the current IA suggest that few pts with GCC-positive metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction experienced limited clinical benefit with TAK-264 treatment. The correlation between GCC levels and clinical outcomes is being explored. Based on the IA, these data do not support continuation of the study. Citation Format: Khaldoun Almhanna, Maria Luisa Limon Miron, David Wright, Antonio Cubillo Gracian, Richard Hubner, Jean-Luc Van Laethem, Carolina Muriel Lopez, Maria Alsina, Federico Longo Munoz, Johanna Bendell, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic. Phase II trial of TAK-264 in previously treated patients (pts) with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expression guanylyl cyclase C (GCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT107. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01577758&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02202759&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom

TAK-264 (formerly MLN0264) is a novel ADC consisting of a human monoclonal antibody that specifically targets GCC, the potent microtubule disrupting agent monomethyl auristatin E (MMAE), and a linker. GCC is selectively expressed in the gastrointestinal (GI) tract, and its expression is maintained through the spectrum of adenoma and carcinoma in the colorectum as well as the pancreas. A Phase 1 clinical trial has demonstrated a manageable safety profile and clinical activity of TAK-264 in patients with pancreatic and gastric carcinomas (NCT01577758). The primary objective of this Phase 2, open-label, non-randomized, multicenter study was to evaluate the overall response rate (ORR; complete response + partial response [PR]), safety, and tolerability of TAK-264 in previously treated adult patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC. Here we report the findings from the interim analysis (IA). Per protocol, the IA was required to show objective responses in at least 2/12 patients with a defined GCC level to continue the second part of this study. Patients aged ?18 years with advanced or metastatic pancreatic adenocarcinoma expressing GCC (confirmed histologically by immunohistochemistry with an H score of ?10) who had received ?1 prior treatment, were eligible for inclusion. TAK-264 1.8 mg/kg was administered as a single 30 minute intravenous infusion on day 1 of a 21-day cycle for up to 1 year or until disease progression or unacceptable toxicity. At data cut-off (October 5, 2015), 43 patients had been enrolled. The median age was 61 years (range, 44-81). Participating patients had metastatic disease and received a median of 3 prior therapies (range, 1-8), with a median time since initial diagnosis of 16.6 months (range, 6-51). Of the 38 patients in the response-evaluable population, the ORR was 3% (PR, n = 1) and 9 patients (24%) had stable disease. A total of 28 (74%) patients experienced progressive disease. All patients received at least 1 dose of TAK-264 and were included in the safety population. The most common adverse events (AE) reported in ?15% of patients were abdominal pain (47%), nausea (37%), fatigue (35%), constipation and decreased appetite (each 28%), vomiting and neutropenia (each 26%), asthenia (21%), and dehydration (16%). Grade ?3 neutropenia, including febrile neutropenia, was reported in 7 (16%) and 2 (5%) patients, respectively. Grade ?3 GI AE included abdominal pain (9%), dyspepsia and vomiting (each 5%), and diarrhea (2%). Overall, a limited number of patients with GCC-positive pancreatic adenocarcinoma showed a modest clinical benefit from treatment with an ADC exploiting MMAE. The correlation between GCC levels and clinical outcomes is being explored. Based on the IA, these data do not support continuation of this study. Citation Format: Khaldoun Almhanna, David Wright, Teresa Macarulla Mercadé, Jean-Luc Van Laethem, Antonio Cubillo Gracian, Carmen Guillén-Ponce, Jason Faris, Carolina Muriel Lopez, Richard Hubner, Johanna Bendell, Alain Bols, Jaime Feliú Batlle, Naureen Starling, Peter Enzinger, Devalingham Mahalingham, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic. A phase II trial of TAK-264, a novel antibody-drug conjugate (ADC), in patients with pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT117.

Background The challenge to improve outcomes for patients diagnosed with advanced pancreatic cancer remains very real with only small improvements in median survival gained by the use of systemic chemotherapy and little improvement in 5-year survival over the past decades. The advent of next generation sequencing (NGS) of tumor nucleic acids has opened up the possibility of improving outcomes through personalized therapies selected on the basis of tumor genetics. Whilst NGS biomarkers can be measured in tumor biopsies sampled shortly before and after treatment this is often not practical for ethical, logistical and simple lack of availability. To circumvent problems associated with tumor sampling we have developed and evaluated blood-borne nucleic acids biomarkers for patients diagnosed with advanced pancreatic cancer. Approach We developed a NGS circulating free DNA (cfDNA) analysis pipeline based on the generation of whole genome NGS libraries followed by sequencing of over 600 cancer-associated genes using Agilent SureSelect. Using whole blood collected with Streck cell free DNA blood collection tubes (cfDNA BCT) we optimised combined circulating tumor cell (CTC) enrichment and cfDNA isolation. Quantitative measurements of KRAS mutations using both NGS and droplet digital PCR (ddPCR) were used to compare the tumor component present in both CTCs and cfDNA. We evaluated the overall approach using External Quality Assessment (EQA) controls and over 50 advanced pancreatic cancer patient samples. For CTC analysis we also compared epitope dependent (CellSearch) and independent (Parsortix) enrichment. Results After applying our NGS pipeline to 5 EQA genomic controls we identified all 14 known mutations correctly indicating high sensitivity and specificity. Both ddPCR and NGS identified KRAS mutations in patient cfDNA with a higher success rate seen for ddPCR consistent with the higher sensitivity of this methodology. From the NGS output additional mutations were detected in samples which either harboured or lacked detectable KRAS mutations. Consistent with previous observations CellSearch CTCs were detected at low levels in around 20% of patients with a similar frequency seen in initial analysis of CTCs obtained by epitope independent enrichment (Parsortix). In general KRAS mutations were detected at a higher level in patient cfDNA compared to enriched CTCs although some patients showed detectable CTC KRAS mutations with no KRAS mutations detected in their cfDNA by either ddPCR or NGS. Ongoing analysis is aimed at establishing if the molecular observations correlate with clinical outcome. Conclusion Combined CTC enrichment and cfDNA isolation is readily achievable using a single Streck cfDNA BCT. Results indicate that combined CTC and cfDNA analysis is more sensitive than either approach alone. Citation Format: Ged Brady, Dominic Rothwell, Mahmood Ayub, Nigel Smith, Sumitra Mohan, Jakub Chudziak, Kyaw Aung, Richard Hubner, Crispin Miller, Alison Backen, Hui Sun Leong, Sakshi Gulati, Chang Sik Kim, Angela Lamarca, Mairéad McNamara, Juan Valle, Caroline Dive. Combined circulating tumour cell (CTC) and circulating tumor DNA (ctDNA) analysis of blood from patients with pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3960.

4089Background: Prognostic markers for risk-stratification of pts with GI-NECs are lacking. We aimed to externally validate our previously-designed prognostic score (Training Cohort [TC]) derived f...

4017Background: Arginine (Ar) depletion is a putative target in HCC, which lacks the citrulline (Ci) to Ar repleting enzyme argininosuccinate synthetase. A is an Ar degrading enzyme cloned from M. ...

e15732Background: nal-IRI is a nanoliposomal formulation of irinotecan. In the primary analysis of the pivotal NAPOLI-1 Phase-3 trial, nal-IRI+5-FU/LV significantly improved median overall survival...

304 Background: Identification of HCC pts with higher probability of benefit from sorafenib warrants investigation. Hypertension (HTN) and hand foot syndrome (HFS) are sorafenib-specific toxicities; the development of these toxicities is prognostic in pts with renal cell cancer receiving sorafenib, their significance in HCC remains uncertain. Methods: HCC pts treated with sorafenib at the Christie NHS Foundation Trust (Nov-09-Feb-15) were identified. The primary end-point was overall survival (OS). Kaplan-Meier and Cox regression models were employed for identification of prognostic factors. Results: Eighty-five eligible pts were identified [median follow-up 6.2 months (range: 0.4-31.4)].Median age 68 yrs (range 29-89); 87% male; 80% background liver cirrhosis ;88% ECOG performance score 0/1; Child-Pugh (CP) A5 (64%), A6 (29%) and B (7%); 41% baseline AFP > 400 IU/L; 45% previous liver-directed therapy. Sorafenib (400mg BD),was started in 68% (median dose intensity 49.9% (range 0.7-100)), remaining patients started at reduced dose. Fifty-one percent had pre-existing HTN (91% treated).The most common grade ≥ 3 treatment-related toxicities were HTN (42% no prior history of HTN), fatigue (8%), and HFS (8%);59% of pts developed any grade HFS and/or worsening HTN (HFS/HTN). Toxicity-related dose reduction/cessation was required in 46 (54%) pts (15% due to HFS, 7% due to HTN). Estimated median progression-free (PFS) and OS were 5.5 (95% CI 4.1-7.0) and 6.5 (95% CI 4.9-8.0) months, respectively. Age at diagnosis, previous liver-directed therapy, CP score, baseline AFP and development of HFS/HTN were included in multivariable analysis: CP-A (vs. B; p-value < 0.001) and development of HFS/HTN (vs. no; HR 0.4 [95% CI 0.2-0.7] p-value 0.001) were independent prognostic factors. The prognostic influence of HFS/HTN was preserved when limiting analysis to pts developing worst grade HFS/HTN in the first 3 months of treatment (53 pts; HR 0.5 [95% CI 0.3-0.9] p-value 0.030) making time-on-treatment bias unlikely. Conclusions: The development of sorafenib-specific toxicities, HFS and HTN, are prognostic factors associated with prolonged OS.

425 Background: CA19-9 has been shown to correlate with response to therapy and OS in patients with mPAC. NAPOLI-1, a randomized phase 3 study evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV compared with 5-FU/LV (29% vs 9%; P=0.0006). Nal-IRI alone did not show a statistical improvement in survival. Methods: Patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 from nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N=417). Unstratified Cox proportional hazards regression was used to estimate HRs and corresponding 95% CIs. Effect of baseline CA19-9 on time to response, progression-free survival, and response will be presented. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. Results show a greater treatment effect on OS with higher CA19-9 level relative to 5-FU/LV. Conclusions: In patients with mPAC previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS supported by progression free survival and objective response rate. The CA19-9 serum level can provide important information with regards to overall survival. Clinical trial information: NCT01494506. [Table: see text]

417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.

Classification of a chemical or chemical product as a primary skin irritant using laboratory animal tests has been defined rigorously and codified in Consumer Products Safety Commission (CPSC) regulations. However, no regulatory agency, including the CPSC, has defined a primary skin irritant threshold for human repeat insult patch tests (RIPTs) that are typically conducted on products, such as cosmetics, anticipated to come into direct contact with humans. Further more, the protocols for animal and human tests are significantly different, as are the schemes for grading responses. Consequently, comparing the results of one type of test with those from the other type has proved to be difficult. In this short communication, we propose a procedure to harmonize the results from these two types of skin irritation tests and suggest that a score of "5" in animal tests, considering 24-h results on unabraded skin, is equivalent to a score of "3" in human RIPTs.

Recent recognition of the high prevalence of neuroendocrine tumors in combination with a sustained failure to improve outcomes for patients with advanced disease has elevated their priority for research and drug development. Sunitinib (SU11248, Sutent; Pfizer Inc. NY, USA) potently inhibits multiple-receptor tyrosine kinases, resulting in antiangiogenic effects. A growing body of evidence indicates angiogenesis is a clinically relevant therapeutic target in pancreatic neuroendocrine tumors, culminating in a Phase III randomized study of sunitinib in patients with advanced progressive pancreatic neuroendocrine tumors. Sunitinib has recently gained regulatory approval as a single agent in this setting, and future studies will investigate most appropriate patient selection, and sequencing and combination with other targeted and cytotoxic agents. Here, we discuss in detail the molecular properties, clinical efficacy and safety of sunitinib in the context of pancreatic neuroendocrine tumors.

Background Creatinine clearance (CrCl) estimation by Cockcroft–Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [ 51 Cr]–ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates. Methods Retrospective analysis of co-morbidity, nephrotoxic drug use, chemotherapy toxicity, and correlation between paired CG and EDTA, in 388 lung cancer and mesothelioma patients receiving platinum-based chemotherapy. Results Potentially nephrotoxic co-morbidity or medication use occurred in 47% of patients, and was twice as likely in those aged >70 years (OR=2.07; 95%CI: 1.25–3.44, p =0.003). Patients with co-morbidity or nephrotoxic medication use had a lower EDTA compared to those without these baseline factors ( p =0.02), but were not significantly more likely to experience chemotherapy toxicity. CG and EDTA correlation was high ( r 2 =0.68), but reduced in patients with ETDA r 2 =0.26, p =0.02) or >120ml/min ( r 2 =0.32, p =0.09), and in those with CG>120ml/min ( r 2 =0.20, p =0.01). The correlation between CG and EDTA was not significantly altered in patients with co-morbidity or nephrotoxic medication use. CG bias (mean percentage error) and precision (mean absolute percentage error, MAPE) were 7% and 26%, respectively, and precision was impaired in patients with abnormally raised serum creatinine (MAPE 65%, p Conclusion CG estimation of CrCl is accurate and safe in lung cancer patients with potentially nephrotoxic co-morbidity or concomitant medication, but should not be used when values are outside the range 50–120ml/min, or with abnormally elevated serum creatinine.

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence.

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome- wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

The UK9s Food Standards Agency recently recommended mandatory folic acid fortification of some foods. Nicholas Wald and Godfrey Oakley argue that it9s a safe effective way of preventing spina bifida and anencephaly—but Richard Hubner and colleagues say that more research into the harms is needed

The majority of colorectal cancer (CRC) exhibiting the micosatellite instability (MSI) phenotype is due to hypermethylation of the hMLH1 gene promoter. We aimed to test the hypothesis that polymorphisms in genes coding for enzymes involved in folate metabolism play a role in altered promoter-specific hypermethylation and thus predispose to MSI CRC. Analysis of MSI was performed in 1685 CRCs, and polymorphism genotypes were determined in germline DNA for all cases and 2692 cancer-free controls. MSI was observed in 171 cancers (10.1%). Compared to homozygous wild-type individuals, those with MTHFR 677TT genotype were more likely to have MSI than microsatellite stable (MSS) CRC [odds ratio (OR) 1.90; 95% confidence interval (CI): 1.09-3.31]. When MTHFR C677T genotype frequencies in MSS CRC cases were compared to controls, individuals with homozygous variant genotype were at 19% reduced risk of cancer compared to wild type (OR = 0.81; 95% CI: 0.65-1.02). Conversely, when MSI CRC cases were compared to controls, individuals with one or two MTHFR 677T alleles were at 42% increased cancer risk (OR = 1.42; 95% CI: 1.02-1.96). Our observations indicate that MTHFR 677TT homozygous individuals are more likely to develop MSI CRC than those with wild-type genotype, and this common polymorphism has differential influences on MSI and MSS CRC risk. Stratification by MSI status should aid future studies investigating the complex relationships between genotype, environmental factors and CRC risk.

Background: Outcomes of patients with high-grade GI-NETs are poor; prognostic markers for risk-stratification are needed.Methods: Consecutive patients, diagnosed with high-grade GI-NETs between 1997-2014, were included. Prognostic factors were identified by the Log-rank test, Cox regression and logistic regression and ROC curve comparisons performed for prediction accuracy. Internal validation of the score by Bootstrap-corrected Harrell Concordance Index (C-index) and Resampling Model Calibration were performed.Results: One-hundred and nine patients were eligible for analysis. Median follow-up time was 9.7 months (1.3-102.9). Median age: 67.7 years (16.3-84.1); 62% male, 84% metastatic; 19% foregut, 5% midgut, 19% pancreas, 28% hindgut and 29% unknown primary. Median ki67: 70% (20-100); ECOG PS 0: 26%, 1: 52%; 70% received chemotherapy. Baseline median alkaline phosphatase (ALK) and LDH were 109 IU/l (45-2035) and 70 IU/l (258-11069), respectively. The maximum model included stage, PS, LDH, Na, ALK, ki67, number of metastatic sites, presence of liver and presence of lung metastases. The score, selected by the lowest Akaike Index Criterion, included liver metastases, PS, ki67, LDH and ALK with 0-6 points assigned to each, resulting in 4 risk groups (A-D) with predicted risk of death, detailed in Table. There was no difference in the survival prediction accuracy between the maximum model and the score. On multivariable analysis, the score was prognostic for overall survival (HR 1.95, 95%CI 1.55-2.47; p < 0.001) and had good discrimination (C-index, 0.76) and calibration (mean error, 0.021; percentile 90, 0.037).Conclusions: This simple score identified high-grade GI-NET patients with meaningful differences in survival and may inform clinical decision-making and trial design.

4102 Background: The PI3K/AKT/mTOR signaling pathway is upregulated in pNET. Everolimus (EVE) is an mTOR inhibitor (mTORi) approved to treat advanced pNET, but resistance occurs. PI3K pathway activ...

234 Background: MM-398 is a nanoliposomal encapsulation of irinotecan. OS in the ITT population was significantly longer with MM-398+5FU/LV over 5FU/LV alone, and the most frequent grade 3+ AEs included neutropenia, fatigue, and GI effects (diarrhea and vomiting). Expanded, pre-specified analyses of the Phase 3 study are presented. Methods: Patients (n=417) with mPAC previously treated with gemcitabine-based therapy, were randomized 1:1:1 in an open-label study to receive: (A) MM-398 (120 mg/m2 IV over 90 min) q3w; (B) 5FU (2,000 mg/m2 over 24 h) plus racemic leucovorin (LV) (200 mg/m2 over 30 min) x 4w followed by 2w rest; or (C) combination of MM-398 (80 mg/m2 IV over 90 min) prior to 5FU (2,400 mg/m2 over 46 h) and racemic LV (400 mg/m2 over 30 min) q2w. The primary endpoint was OS. The Intent To Treat (ITT) population included all randomized patients; the Per Protocol (PP) population included patients who received at least 80% of the target dose in the first 6 weeks and did not violate any inclusion/exclusion criteria. Results: Analysis of the PP populations confirmed the favorable OS, which was also reflected by the PFS, ORR and CA19-9 levels, of the combination MM-398+5FU/LV arm over the control 5FU/LV arm. The MM-398 monotherapy arm did not show a statistically significant improvement in OS compared with the control arm. Analysis of subgroups, based on pretreatment characteristics including stage at diagnosis, time since initial histological diagnosis, prior lines of therapy, time since last prior therapy, and CA19-9 levels, consistently favored OS for the MM-398+5FU/LV arm over the 5FU/LV arm. Conclusions: Expanded analysis of the PP population and sensitivity analyses support the favorability of MM-398+5FU/LV over 5FU/LV, with a manageable safety profile. Clinical trial information: NCT01494506. [Table: see text]

MTHFR C677T and colorectal cancer risk: a meta-analysis of 25 populations The common functional methlylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the risk of colorectal cancer (CRC), but data from published studies with individually low statistical power are conflicting. To clarify the role of MTHFR C677T genotype in CRC, we considered all available studies in a meta-analysis. Studies reporting on MTHFR C677T genotype and CRC were searched in PubMed up to April 2006. The principle prior hypothesis was that homozygosity for MTHFR 677TT would be associated with reduced risk of CRC. Data were available for 29,931 subjects, including 12,243 with CRC, from 25 independent populations. Compared to the homozygous CC genotype, the MTHFR 677TT genotype was associated with a reduced risk of CRC (odds ratio (OR): 0.83; 95% confidence interval (CI): 0.75-0.93; p = 0.001). There was some heterogeneity among the results of individual studies, but this was not statistically significant (heterogeneity p = 0.12; 12 = 25.8%). Heterozygosity for MTHFR 677 did not influence CRC risk (OR: 0.99; 95%, CI: 0.94-1.04). These findings indicate that individuals homozygous for the MTHFR 677TT genotype are at moderately reduced risk of CRC, and support the proposal that common genetic variation in the MTHFR gene contributes to CRC susceptibility, probably accounting for at least 9% of the total incidence. (c) 2006 Wiley-Liss, Inc.

Purpose A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies. Methods Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques. Results Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I2 = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14). Conclusion CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.

Aim: The mTOR inhibitor everolimus is approved for the treatment of patients with advanced pNet but resistance can occur. BEZ235 (BEZ) is an oral, dual inhibitor that targets class I PI3K and downstream effectors mTORC1/2. Here we present interim Stage I (open-label, single-arm) results of a multicenter, 2-stage, Ph II study of BEZ in patients with advanced pNET that had progressed on everolimus (NCT01658436). Methods: Patients with unresectable/metastatic histologically confirmed low/intermediate-grade pNET with radiologic evidence of disease progression since last treatment and refractory to everolimus were enrolled. The starting dose of BEZ was 400 mg twice daily (BID), which was reduced to 300 mg BID due to the safety/tolerability profile. The primary objective of Stage I was to evaluate the efficacy of BEZ based on the progression-free survival (PFS) rate at 16 weeks (RECIST v1.1). Futility was shown if the observed 16-week PFS rate was Results: Between Nov 2012 and Sep 2013, 31 patients were enrolled and treated with BEZ 300 mg BID (n = 20) or 400 mg BID (n = 11). Median duration of exposure was 16 (range: 2–43) weeks. Seven patients were ongoing at data cut-off on Jan 16, 2014; the most common reason for discontinuation was adverse events (AEs; 39%) followed by progressive disease (36%). The 16-week PFS rate was 48% (90% CI 33–64), and the posterior probability that the PFS rate was ≥40% was 82%. Stable disease (SD) was achieved by 15 patients at Week 16 and 9 patients had progressive disease. The most frequent (≥10%) Grade 3/4 AEs regardless of causality were hyperglycemia (36%), and diarrhea, nausea, and gamma-glutamyltransferase increase (18% each) at BEZ 400 mg, and hyperglycemia (10%) at BEZ 300 mg. Conclusions: At 400 mg, BEZ was not tolerated in this patient population who had progressed on everolimus; 300 mg/day was better tolerated, with most AEs being mild to moderate. Preliminary evidence of activity was observed, with 48% of patients achieving SD after 16 weeks of treatment. Due to high discontinuation of treatment due to AEs and early disease progression, the primary objective of Stage I was not met and the study will not proceed to Stage II. Disclosure: N. Fazio: Advisory board for Novartis, Ipsen, Pfizer, Lexicon; R. Buzzoni: Received grants from: Novartis, Italfarmaco, Ipsen; E. Baudin: Advisory board/honoraria from Novartis, Ipsen, Pfizer, Roche; R. Hubner: A member of remunerated Novartis sponsored advisory boards; H. Lahner: Lectures: Novartis, Pfizer Grant received: Novartis Advisory board: Novartis, Pfizer; W.W. De Herder: Participated in advisory boards for Novartis and Ipsen; M. Raderer: Received honoraria from: Novartis, Roche, Ipsen, Pfizer, Bayer, Celgene; A. Teule: Data monitoring board for the Catalan Institute of Oncology, and received grants and personal fees from Novartis; M. Kulke: Consulted for Novartis; M. Shah: Received research funding from Novartis; D. Dey: Employee of Novartis; S. Turri: Employee of Novartis; P. Aimone: Employee of Novartis; Verslype: Received research funding from Novartis. All other authors have declared no conflicts of interest.

Aim: Fibroblast growth factors (FGFs) and their receptors (FGFRs) control a wide range of biological functions, and are implicated in the pathogenesis of diverse tumour types including gastro-oesophageal adenocarcinoma (OGA). AZD4547 is a potent, selective, small molecule inhibitor of FGFR 1, 2, & 3 tyrosine kinases. The aims of the phase I component of this study were to determine the safety, MTD, & PK profile of AZD4547 when administered with cisplatin (C) and capecitabine (X). Methods: Eligible patients (pts) with refractory advanced solid tumors, adequate performance status (PS), haematologic, renal, hepatic function received 1 of 3 escalating doses of AZD4547 in a “rolling six” dose escalation design. AZD4547 was administered orally (po) bid days 1-14 in combination with C (80 mg/m2 i/v) and X (1000 mg/m2 po bid days 1–14) in 3-weekly cycles. DLTs were based on cycle 1 toxicities which were assessed weekly (clinical, haematologic, biochemical) with ophthalmic assessment and echocardiogram at 4 weeks. Plasma AZD4547 was measured in blood over 24 hrs (day 1). Disease (CT scan) was assessed 9-weekly. Results: 19 pts (11 M, 8F), median age 57 (range: 40-78) were enrolled; 16 with PS 0 (9) or 1 (7) were evaluable for toxicity at 40mg BD (4 pts), 60mg BD (6), or 80mg BD (6) dose levels. Median duration of treatment was 3 cycles (range: 1-6). 4 DLTs occurred in 3 pts: 3 DLTs at 80mg BD (grade 3/4 neutropenia with fever; & > 2 week dose interruption for cardiac toxicity; - 1 pt; grade 3 LFT elevation – 1 pt); 1 DLT at 60mg BD (grade 3 oral mucositis). Cumulative (worst grade, all cycles) grade 3/4 toxicities (excluding DLTs) included hypomagnesaemia (5 pts), electrolyte disturbance (4) neutropenia (3), pulmonary embolism (3), elevated AST / ALT (3), nausea (2), febrile neutropenia (1). 1 partial response (basaloid cervical cancer) was observed at 40mg BD. Stable disease was observed in 7 pts at 9 weeks and in 3 pts at 18 weeks. Conclusions: The recommended dose of AZD4547 is 60mg BD when combined with CX. A randomised phase IIa study of CX + AZD4547 or placebo is on-going in patients with advanced OGA and polysomy or amplification of FGFRs. Disclosure: D. Landers: Employee of AstraZeneca UK Limited, involved in development of the reported drug. All other authors have declared no conflicts of interest.

TPS1617 Background: Pre-clinical data demonstrate that aspirin inhibits tumour growth and prevents metastases. Meta-analyses of individual patient data from randomized trials evaluating cardiovascu...

In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.

Objectives Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat. Design and methods In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125 I-RB104 and the specific ACE inhibitor radioligand 125 I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point). Results Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC 50 305 ± 5.4 nmol/l) and ACE (IC 50 3.6 ± 0.02 nmol/l). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P < 0.01), and renal ACE and NEP (3,10 mg/kg, P < 0.01). In the time course experiment gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P < 0.01) and inhibited plasma ACE (P < 0.05), renal NEP (P < 0.01) and renal ACE (P < 0.05) for 48 h. Conclusions Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.

TPS4160 Background: While sorafenib is established as the standard first-line treatment for patients with advanced HCC, its use can be complicated by the occurrence of drug-related adverse events (AEs). Nintedanib, a potent, oral triple angiokinase inhibitor that targets VEGF, PDGF and FGF signaling (as well as Flt3 and RET), has demonstrated clinical activity in various advanced solid tumors with a relatively low incidence of AEs typically associated with angiogenesis inhibitors (e.g. skin toxicity, hypertension, hemorrhage, and hematologic toxicity) and is currently in phase III for non-small cell lung cancer and ovarian cancer. In the Phase I, dose-finding stage of this ongoing, multicenter, open-label Phase I/II trial (NCT01004003), 200mg twice daily (bid) was established as the maximum tolerated dose of nintedanib in previously untreated patients with advanced HCC (Palmer D, et al. Ann Oncol 2012;23(Suppl 9):ix245[Abs 740P]). Nintedanib had an acceptable liver AE profile; the most common AEs were mild/moderate gastrointestinal toxicities. Methods: The randomized Phase II stage of the trial aims to assess the efficacy, safety, and pharmacokinetics of nintedanib in comparison with sorafenib. Eligible patients have pathologically confirmed, measurable HCC that is not amenable to local therapy, ECOG Performance Status of ≤2, Child-Pugh score of 5–6 (Class A), AST/ALT levels ≤2× upper limit of normal, and no prior systemic therapy. Patients are being stratified by macrovascular invasion and/or extrahepatic spread and then randomized 2:1 to receive nintedanib 200mg bid or sorafenib 400mg bid in continuous 28-day cycles until progression or unacceptable toxicity. Overall, 93 patients were randomized between Sept 2011 and Nov 2012. The primary endpoint is time to progression (TTP) by independent review, according to RECIST 1.0. TTP will be estimated in the treated set by Kaplan–Meier methodology with treatment effects compared using a Cox proportional hazards model. Secondary endpoints include overall survival, tumor response, progression-free survival, safety and pharmacokinetics. Results are due late 2013. Clinical trial information: NCT01004003.

6 Background: There are no randomised trials of 2nd line chemotherapy for esophageal cancer. The phase III COG trial of gefitinib versus placebo in patients with esophageal cancer progressing after chemotherapy did not show significant overall survival (OS) benefit, however the trial incorporated patient reported outcomes (PRO) using validated tools. The PRO data are therefore critical to inform practice and the initial results are presented here. Methods: Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: OS. Secondary outcomes include safety, PFS, PRO (assessed by EORTC QLQ-C30 and EORTC QLQ-OG25 at baseline 4, 8 and 12 weeks until progression) and predictive biomarkers. Pre-specified PRO domains were global quality of life, dysphagia, eating and odynophagia. Analysis by ANCOVA of change in PRO at 4 weeks adjusted for baseline. Results: 450 patients were recruited from 51 UK centres and no difference in OS was detected. There was evidence that PFS was better in the intervention arm (P 35 days, G 49 days; HR=0.795, 95%CI 0.66, 0.96, p=0.017). Questionnaire compliance rates were excellent at baseline (94%) and at 4 weeks (77%). Patients in the gefitinib arm reported significantly better social function (9.26; 95%CI 1.94 to 16.58; p=0.013) and significantly fewer problems with odynophagia (-8.61; 95%CI -14.49 to -2.73; p=0.004), constipation (-15.24; 95%CI -22.83 to -7.65; p=0.0001) and speech (-10.40; 95%CI -16.13 to -4.67; p=0.0004) than patients receiving placebo but more problems with diarrhoea (19.23; 95%CI 11.79 to 26.27; p

Introduction Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are uncommon tumours occurring at all sites within the gastrointestinal tract. The behaviour of these tumours is difficult to predict and they have been subject to numerous changes in classification and grading systems. In the UK the National Institute for Clinical Excellence recommends centralised histopathology review of these tumours by a member of the NET tumour board. We aimed to determine the frequency of discrepancies between local and central histopathology that could impact clinical management. Methods We identified 86 cases of suspected GEP NET referred for specialist histopathology review at the regional network centre from January 2010 to April 2012. Cases were identified by a SnoMed search for cases coded under various endocrine tumour designations and by cross referencing with patient lists from multidisciplinary team meetings. Details of the local and network centre pathology reports were compared. The reports were also judged for compliance with the UK Royal College of Pathologists minimum dataset. Results There was complete diagnostic agreement in 54 cases (63%). Discrepancies occurred in the remaining 32 cases (37%), including, 18 differences in grade or proliferation index score (21%), 16 differences in nomenclature (19%), 6 differences in stage (7%) and 5 differences in assessment of perineural or vascular invasion (6%). In 9 cases (10%) an original diagnosis of endocrine tumour was changed to a different type of tumour without endocrine differentiation or vice versa following review. Twenty-six of the overall discrepancies (30% of the total cases) had the potential to meaningfully impact on clinical management. In addition, neither tumour grade nor proliferation index were recorded in 15 local pathology reports (17%), which would necessitate additional pathological analysis prior to clinical decision making. There was full adherence to the minimum dataset in only 19 cases (42% of resections). Conclusions This study highlights the importance of specialist centre histopathology review of GEP NET to ensure these patients receive the appropriate clinical management. Disclosure All authors have declared no conflicts of interest.

Background There is no standard systemic therapy for metastatic esophageal cancer progressing after 1st/2nd line chemotherapy (Thallinger et al, 2011, JCO, 4709-14). High EGFR expression is associated with poor prognosis in esophageal cancer. A phase II trial of the EGFR kinase inhibitor gefitinib showed good tolerance with 11% partial responses and a trend towards improved survival (Ferry et al. Clin Cancer Res 2007, 13: 5869-75). Four other phase II trials showed objective responses with gefitinib or erlotinib. Cancer Research UK funded this pivotal phase III trial with free study drug provided by Astra Zeneca UK. Methods Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status (PS) 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: overall survival (OS) - an increase from 10-18% in 1yr OS is detectable with 450 patients, power 82.5%, significance level 5%, analysed with Kaplan-Meier and log-rank test. Secondary outcomes include safety, PFS, HRQL (EORTC QLQ-C30 and QLQ-OG25) and predictive biomarkers. Results Recruitment of 450 patients from 51 UK centres occurred Mar 2009-Nov 2011. Baseline characteristics were well-balanced - median age 64 years; 83% male; 76% adenocarcinoma; 78% esophageal; PS0 25%, PS1 54%, PS2 21%. Median PFS was P 35 days, G 49 days (HR = 0.795, 95%CI 0.66, 0.96, p = 0.017). Median OS was P 3.60 months, G 3.73 months (HR = 0.90, 95%CI 0.74, 1.09, p = 0.285). No significant safety concerns emerged. PS is a highly significant prognostic factor for both PFS (median PFS: PS0 1.8, PS1 1.4, PS2 1.0 months) and OS (median OS: PS0 6.0, PS1 3.9, PS2 2.0 months). Disease control rate at 8 weeks in patients with measurable disease was P 16.0%, G 25.5% (p = 0.014). HRQL was assessed for the pre-specified outcomes of QoL, dysphagia, eating and odynophagia, the latter of which was improved for gefitinib (p = 0.004). Conclusion COG is the first large randomised trial in the 2nd/3rd line setting in esophageal cancer. Although the primary OS endpoint was not acheived, there was significant PFS improvement and palliation. Durable responses were seen, and the translational study (Trans-COG) is investigating the correlation of benefit with biomarkers. Disclosure D.R. Ferry: Consultant role for Astra Zeneca Honoraria from Astra Zeneca Research funding from Astra Zeneca M. Harrison: Wife has shares in Astra Zeneca. Otherwise no conflicts of interest A. Chatterjee: Received and honoraria for a presentation on gefitinib. otherwise no conflicts of interest A. Garcia-Alonso: A consultant/advisory role for Roche. otherwise no conflicts of interest J. Jankowski: Consultant to AstraZeneca. No other conflicts of interest R.D. Petty: Consultant for Roche and Astra Zeneca (compensated) Honoraria from Roche and Pfizer Research funding from Roche All other authors have declared no conflicts of interest.