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PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non–small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.

TPS9138 Background: Lung cancer is the most common cause of cancer-related death worldwide with over 1.6 million deaths per year. Non-small cell lung cancer (NSCLC) accounts for 80% of cases, the majority of which are adenocarcinomas. 75% of patients present with inoperable tumours and/or with distant metastatic spread, with 5-year survival for stage IV disease as low as 5%. Treatment options include chemotherapy, targeted therapies for specific mutations, and - increasingly - immune checkpoint inhibitors (CPI). Adoptive cell therapies (ACT) can produce durable responses in pre-treated NSCLC. Evidence also suggests potential benefit of combining ACT with CPIs, even after acquired resistance. Efforts to improve efficacy include the expansion of T cells able to recognise patient-specific clonal tumour neoantigens. Clonal tumour neoantigens arise early in cancer evolution and represent a subset of patient-specific mutations present in all cancer cells. Developing ACTs that target clonal neoantigens represents a personalised approach to treating all cancer cells concurrently, minimising the risk of tumour escape and reducing potential for off-target toxicities. Insights gained from applying the PELEUS bioinformatic platform (developed using UK TRACERx study data) to matched tumour and blood samples from NSCLC patients – as part of a tissue acquisition study (NCT03517917) – has enabled the manufacture of a personalized clonal neoantigen-reactive T cell (cNeT) product (ATL001), which is now in clinical development. Methods: The CHIRON Study (NCT04032847), is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical activity of ATL001 administered intravenously in up to 40 adults with advanced unresectable or metastatic NSCLC. Following consent and screening, patients enter the study for procurement of tumor tissue and blood to manufacture ATL001. Tissue may be procured during treatment with standard systemic therapies. Patients in Cohort A receive cyclophosphamide/fludarabine on days -6 to -4, followed by a single dose of ATL001 and 10 daily doses of subcutaneous IL-2; Patients in Cohort B will additionally receive one dose of pembrolizumab between days -13 and -6 before receiving ATL001, then restart pembrolizumab 2 weeks after receiving ATL001 and continue for up to 12 months. Key eligibility criteria include treatment with at least one prior systemic therapy (including a PD-1 inhibitor). Primary endpoints are the safety and tolerability of ATL001 as a monotherapy and in combination with pembrolizumab. Secondary endpoints include change in tumor size and response rate by RECIST 1.1 and imRECIST. Correlative studies will investigate the effects of cNeT dose and engraftment kinetics on clinical activity. The study began enrolling patients in Cohort A in August 2019. Clinical trial information: NCT04032847.

LBA4006 Background: The ESPAC-3 trial compared adjuvant GEM with 5-fluorouracil/folinic acid for resected pancreatic cancer. GEM is the standard of care based on similar survival and less toxicity. ESPAC-4 aimed to determine whether combination chemotherapy with GEM/CAP improved survival compared to GEM monotherapy. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4 week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was overall survival; secondary endpoints were toxicity, relapse free survival, 2 and 5 year survival and quality of life. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2 year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 60% were R1 resections, 80% were node positive and 40% were poorly differentiated. On Dec 11 2015 the Independent Trial Steering Committee requested that the trial proceed to full analysis. The data freeze was on March 2 2016. Median survival (months) for patients treated with GEM/CAP was 28.0 (95% CI, 23.5 – 31.5) and 25.5 (22.7 – 27.9) for GEM. Stratified log-rank analysis revealed an HR=0.82 [95% CI, 0.68 – 0.98]; χ2 (1) = 4.61, P=0.032. 196 out of 366 GEM patients in the safety set reported 481 grade 3/4 adverse events, while 226 out of 359 GEM/CAP patients reported 608 grade 3/4 adverse events ( P=0.242). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: ISRCTN96397434.

3580 Background: The multicenter, open-label, randomized, phase 3 EPIC study (EMR 062202-025) investigated cetuximab + irinotecan vs irinotecan as a second-line (2L) therapy in pts with EGFR-detectable mCRC. A retrospective analysis in the EPIC RAS wt population showed improved overall response rate (29.4% vs 5.0%) and progression-free survival (5.4 vs 2.6 mo) upon the addition of cetuximab to irinotecan. Median OS (mOS) was similar in both treatment arms, possibly due to differences in subsequent therapies. We present OS by post-study therapy in the RAS wt population. Methods: 1298 RAS-unselected pts were enrolled from May 2003 to February 2006. The primary endpoint was OS. RAS status was determined retrospectively in 2018 from existing DNA samples using BEAMing technology; wt status was defined as having a sum of mutated RAS allele frequencies of ≤5%, with all relevant alleles being analyzable. Results: Among the 452 pts with RAS wt mCRC, 231 received cetuximab + irinotecan and 221 received irinotecan. Baseline characteristics were similar in both arms. OS data by post-study therapy are summarized in the Table. No new or unexpected safety signals were observed. Conclusions: Post-study cetuximab was associated with improved OS in both treatment arms compared with post-study therapy without cetuximab and no subsequent therapy, suggesting that cetuximab-based therapy may be suitable as a standard treatment for pts with RAS wt mCRC in the rechallenge setting. Study limitations include a potential bias due to the differences in proportion of subsequent therapies with and without cetuximab between arms (almost 50% of pts in the irinotecan arm received post-study cetuximab) as well as the likelihood for pts who live longer to receive cetuximab in any subsequent therapy line. [Table: see text]

6049Background: Genomic characterisation of head and neck cancer (HNC) has identified 3-5 subgroups with distinct biological properties, including metabolic profile and immune status. Both facets c...

TPS9099 Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study of patients with radically resected primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through genetic analysis of multi-region and longitudinal tumour sampling. DARWIN II is an investigator initiated study for patients who are enrolled within the TRACERx trial, or who have multi-region sequencing of their primary disease, but subsequently relapse with metastatic disease. This study will examine the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy. Methods: This multicentre non-randomised phase II molecularly stratified umbrella study will examine how clonal dominance and ITH influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between ITH and cfDNA/CTCs will also be explored in DARWIN II. The study arms: Arm 1: Patients either -1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy - Atezolizumab. Arm 2: BRAFV600 - Vemurafenib. Arm 3: ALK/RET gene rearrangement - Alectinib. Arm 4: Her2 Amplification - Trastuzumab Emtansine. Primary Outcome Measures: Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death will be assessed according to: Neo-antigen burden, mutational burden, ITH as assessed using an ITH ratio index and genomic instability as assessed using a weighted genome instability index (wGII). Trial Sponsor: University College London. Clinical trial information: NCT02314481.

2548 Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours and interact to promote tumour growth and therapeutic resistance. Activity of single pathway inhibition is limited due to compensatory activation of alternative signalling pathways. Dual pathway inhibition has demonstrated synergistic activity in preclinical models, with broad activity across a range of molecular backgrounds. This study was designed to evaluate the optimal doses and schedule of vistusertib (dual mTOR1/2 inhibitor) and selumetinib (MEK1/2 inhibitor) when given in combination. Methods: Thisphase Ib/IIa trial with a dose escalation part (Ib) in treatment refractory advanced solid tumours and expansion cohorts in TNBC, squamous and non-squamous NSCLC (KRASmt & WT) (IIa). Both, continuous daily (CC) (25, 35, 50mg BD) and intermittent (IC) schedules (50, 100, 125mg BD 2ds on, 5 ds off) of vistusertib were investigated. Selumetinib dose was given at a dose of 75mg BD daily. Treatment was given until PD (RECIST 1.1) or intolerable toxicity. The primary endpoint was DLTs. Secondary endpoints included response, clinical benefit, PFS and PK. Results: 23 evaluable patients were enrolled in the PhaseIb part. For the intermittent schedule, no DLTs were reported at any of the dose levels IC1-3. For the continuous schedule, 2 out of 9 patients treated at dose level C2C developed DLTs (G3 mucositis, dizziness and rash). Dose level C3C was not tolerated with DLTs observed in 2 out of 3 patients (G3 mucositis and G3 LFTs). Separate MDTs were determined for intermittent (I3C) and continuous schedules (C2C). Adverse events were in keeping with established single agent safety profiles. Anti-tumour efficacy was demonstrated at various dose levels and across tumour types including uveal melanoma, breast, cervical, uterine, skin or colorectal cancers. There were no objective responses but confirmed stable disease for > 16 weeks were observed in 7 patients with a duration of response ranging up to 55+ weeks. Conclusions: Based on DLTs, dose intensity and cumulative toxicity, the intermittent schedule I3C was selected as RP2D for expansion cohorts. Preliminary anti-tumour activity was observed. Clinical trial information: NCT02583542.

3561Background: RAS mut status predicts lack of benefit from anti-EGFR agents in aCRC, but its impact on prognosis and chemotherapy outcomes is less clear. Previously we have reported that the poor...

9026Background: The anti–PD-1 antibody pembro (MK-3475) is approved in the US for treating PD-L1–positive NSCLC that progressed after platinum-containing chemotherapy. This approval was based on da...

TPS8111 Background: Outcomes remain poor in patients with non-small cell lung cancer (NSCLC) of squamous origin. There are few established therapeutic targets, and benefits of chemotherapy are freq...

3509 Background: BRAF-mut aCRC pts have poor overall survival (OS). To investigate this phenomenon, we have examined individual patient data from pts treated with chemotherapy alone in 3 RCTs to id...

4121 Background: The TeloVac trial randomized 1,062 patients with advanced pancreatic cancer to a control chemotherapy Arm1, using GemCap; sequential chemoimmunotherapy Arm 2, GemCap for 8 wks foll...

4067 Background: REAL3 evaluated EOC + P in advanced oesophago-gastric adenocarcinoma. We previously reported that addition of P was associated with increased diarrhoea, skin rash and mucositis wit...

91 Background: The REAL3 trial evaluated the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. We previously reported that addition of panitumumab was not associated with improvement in survival endpoints. In this analysis we aimed to explore factors associated with OS in the REAL3 population. Methods: Analysis performed in ITT population (n=553). OS was evaluated in relation to the baseline characteristics displayed in the table below. Cox regression was used to obtain HRs and 95% CIs. Factors with p100 U/L. Results: Results of the univariate analysis are shown in the table below. In multi-variate analysis, the factors which remained statistically significant for OS were: PS (p=0.080): 1 vs 0 HR 1.24 (95% CI 0.99-1.57); 2 vs 0 HR 1.57 (95%CI 0.97-2.54) Disease extent (p=0.054): Met disease vs LA HR 1.42 (95% CI 0.99-2.02) Baseline global health score (p=0.005): Low vs high HR 1.52 (95% CI 1.16-2.00); middle vs high HR 1.45 (95% CI 1.11-1.89) Patients with an RMH Prognostic Index score of 0 (good prognosis) had median OS of 13.1 mo. This compared to 9.5 mo in patients with 1-2 adverse features (intermediate prognosis) (HR 1.37, 95% CI 1.12-1.68; p=0.002) and 4.7 mo in patients with 3-4 adverse features (poor prognosis) (HR 4.02, 95% CI 1.96-8.22; p

7595 Background: Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in order to determine if overall survival (OS) was affected by the addition of pravastatin in SCLC. Methods: Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity. Results: Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed > 4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Updated results showing OS, PFS, local PFS and toxicity will be presented. Conclusions: This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients. Clinical trial information: ISRCTN56306957.

4023 Background: Survival in patients who relapse after first-line chemotherapy (CT) for advanced esophago-gastric adenocarcinoma (EGC) is poor though recently randomised trials (RCT) have suggested a small benefit for second line chemotherapy with taxanes or irinotecan. There is very little data on health related quality of life (HRQL) or overall survival (OS), particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicentre open-label, phase III RCT for patients with locally advanced or metastatic EGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine CT. Patients were randomised (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC). The primary endpoint was OS. The secondary endpoint of HRQL, assessed using EORTC QLQ-C30 and QLQ-ST022, was analysed using standardised area under a curve and compared using Wilcoxon rank sum test. Sensitivity analysis adjusting for dropouts due to death were performed using quality adjusted survival. Results: 168 patients (84 patients in each arm) were recruited between April 2008 and April 2012. Median age was 65 years (range 28-84); 81% were males. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. Median number of cycles of docetaxel was 3. 23% completed 6 cycles. Docetaxel was well tolerated and resulted in a significantly improved OS over ASC alone (HR=0.67 (95% CI 0.49-0.92); p=0.01). Objective response rate was 7%. For QLQ-C30, patients on docetaxel arm reported significantly less pain (p=0.0008) and trend for less nausea and vomiting (p=0.02) and constipation (p=0.02) than those on ASC arm. Similar global HRQL seen (p=0.53).For QLQ-ST022, trend seen for less dysphagia (p=0.02) and pain symptoms (p=0.01) for patients on docetaxel arm than ASC Conclusions: Docetaxel provided a significant OS benefit over ASC with improvements in symptom scores and no loss in overall HRQL. Docetaxel can be considered a standard of care in this setting. Clinical trial information: NCT00978549.

TPS3645 Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarker-based subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.

LBA4004 Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs. Methods: Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided α=0.025 level of significance with at least 80% power. Results: 1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1). Conclusions: OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p

LBA4 Background: Survival in patients who relapse after first-line chemotherapy for advanced esophagogastric adenocarcinoma (OGC) is poor though recently randomized trials have suggested a small survival benefit for second-line chemotherapy with taxanes or irinotecan. There is very little data on quality of life or survival, particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicenter open-label, randomized controlled phase III trial for patients with locally advanced or metastatic OGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine (PF) chemotherapy (CT). Patients were randomized (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC), which could include any treatment thought by the treating clinician to be appropriate for the management of symptoms including radiotherapy, steroids and supportive medications. The primary endpoint was overall survival. Secondary endpoints were response rate, toxicity, health related quality of life (HRQL) and healthcare resource use. Results: Between April 2008 and April 2012, 168 patients were recruited (84 patients in each arm). Median age was 65 years (range 28-84), 81% were male. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. Site of disease was stomach in 46%, esophagogastric junction in 34% and esophagus in 20%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. 19 (23%) patients completed 6 CT cycles (median 3 cycles per patient). The main reasons for not completing treatment were progression and toxicity. Docetaxel significantly improved overall survival over ASC alone (median 5.2 months (95% CI 4.1-5.9 months) for docetaxel; 3.6 months (95% CI 3.3-4.4 months) for ASC, HR=0.67 (95% CI 0.49-0.92); p=0.01). 7% had a partial response and 46% had stable disease after CT. 21% on docetaxel had grade 4 toxicity. Conclusions: The addition of docetaxel to ASC significantly improved overall survival. Docetaxel can be considered a standard of care in this setting. Clinical trial information: 13366390.

4 Background: Research investigating Pts’ preferences in treatment (tx) decisions for advanced (NSCLC) has generally been limited to smaller, single-country studies or anecdotal reports, and has rarely included Cgs’ perspectives. Methods: A 30 minute online or phone survey was conducted 28 June to 9 August, 2011. Survey participants (SP) included NSCLC Pts (n=245) or Cgs of NSCLC Pts (n=251) treated in the prior 12 months. A 1:1 non-paired sample of Pts and Cgs was sought in the US (n=295), France (FR; n= 100) and Germany (DE; n=101). FR and DE data were weighted to better reflect the age distribution of NSCLC in those countries, then combined. Results: For NSCLC SP, 64% were ≤65 years; 52% were male; 13% current smokers; 64% former smokers. Disease was localized in 21%, advanced in 73% and unknown in 6%. Tx was ongoing in 54%, and in 15% and 31% respectively tx was completed < 3 or 3-12 months previously. SPs elected tx to maintain independence (90%) and to control the cancer (89%); 81% were willing to continue tx indefinitely to maintain disease control. Although 69% of SP were greatly concerned about chemotherapy side effects, 60% were willing to endure significant side effects to live longer. SPs were comfortable asking their doctor questions (84%), and 68% were comfortable asking questions if they disagreed with recommended tx; 58% of SPs usually deferred tx decisions to the doctor. Comprehension of the tx plan was higher upon tx initiation (71%) than at diagnosis (46%) or at time of initial explanation by the doctor (62%). Many SPs (77%) relied on the nurses to help them understand their condition/tx. Among SPs in whom tx was discontinued (n=230), the most common reported reasons for stopping were that the cancer decreased in size (41%) or had stopped growing (28%). Only 14% believed tx was stopped because the cancer was not responsive, while 13% believed the cancer was gone. Conclusions: This large 3-country survey characterized factors important to the NSCLC SP in determining motivations for tx including a desire to control the disease and willingness to continue treatment for disease control if there was an acceptable risk/benefit balance. The survey also indicated a possible misapprehension on the reason(s) tx was halted.

TPS4143 Background: Perioperative ECX chemotherapy is a standard of care for localised gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham NEJM 2006). B is a monoclonal antibody targeting VEGF-A, and in combination with chemotherapy results in improved response rates (RR) and progression free survival in advanced gastric cancer (Ohtsu JCO 2011). The aim of ST03 is to assess the safety and feasibility (stage I, first 200 pts) and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. Methods: ST03 is a multicentre, open-label, phase II/III randomised trial ongoing at 92 UK centres; sites in Germany will open in 2012. Eligibility criteria are histologically proven, untreated, resectable, lower oesophageal, OGJ or gastric adenocarcinoma; age ≥18 years; WHO PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are TIA/CVA or MI ≤1 year; uncontrolled hypertension; ≥Grade II NYHA heart failure; recent gastrointestinal inflammatory conditions or major surgery/trauma/open biopsy 2 iv D1, cisplatin 60 mg/m2 iv D1 and capecitabine 1250mg/m2/D1-21) +/- B 7.5mg/kg D1 q3wk during chemotherapy, then 6 Bev q3wk (investigational arm). Surgery is pre-specified and laparoscopic procedures allowed only after quality assurance review. All specimens undergo central pathology review; blood and tissue collection for translational correlates is ongoing. The primary outcome measures for Stage I (safety results including cardiac EF) have been reported (Okines ASCO 2011). The stage II primary outcome measure is overall survival. Secondary outcome measures are RR, resection rate, disease free survival, toxicity, and QoL. An MRI substudy is open, a PET substudy is planned. 558 of ~950 pts required have been recruited, accrual expected to complete in 2013. An embedded pilot study within ST03 randomising HER2 positive patients to ECX ± lapatanib will open in 2012. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and funded by Cancer Research UK (CRUK06/025, NCT00450203).

LBA4000 Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. Methods: Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. Results: 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 months with mEOC+P (HR 1.37: 95% CI 1.07-1.76, p=0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 95% CI 0.98-1.52, p=0.068), with RR being 42% compared to 46% (odds ratio 1.16: 95% CI 0.81-1.57, p=0.467). mEOC+P was associated with ↑ G3/4 diarrhoea (17% vs 11%), skin rash (14% vs 1%) and thrombotic events (12% vs 7%), but ↓ haem toxicity (>G3 neutropenia 14% vs 31%). In the mEOC+P arm, OS was significantly improved in patients with G1-3 rash (77%, n=209) on treatment compared to those without (23%, n=63); median OS 10.2 vs 4.3 months (p

2613^ Background: Afatinib (BIBW 2992) is an oral, irreversible ErbB family blocker. This trial prospectively evaluated the possible proarrhythmic potential of afatinib by assessing QTc interval, as well as its PK and clinical efficacy. Methods: Patients (pts) with tumors known to overexpress EGFR or HER2, including those with brain metastases and GBM were eligible for treatment with daily afatinib 50mg. Pts with a QTcF-interval >470 ms, a PR-interval >230 ms, a QRS-interval >120 ms and ST-segment and T/U-wave abnormalities at screening, as assessed by central cardiology review, were excluded. 60 pts were treated. Time-matched 24-h ECGs were performed prior to drug exposure, after single dose and at steady state. Pharmacokinetic (PK) samples were drawn on days coincident with ECGs. Results: 49 of 60 pts were analyzed for the QTcF. The largest mean time matched QTcF change from baseline to Day 14 was 1.6 ms (90% CI –2.1, 5.2) at 1 h post dosing. The analysis of the relationship between the afatinib concent...

3523 Background: Phase III trials show inconsistent effects when anti-EGFR drugs are added to cytotoxic therapy in aCRC. Benefits, when present, are confined to patients (pts) determined retrospect...

3566 Background: Phase I/II data showed that ciclosporin (Cs) profoundly reduces the hepatobiliary clearance of irinotecan (Ir), and suggested that 40% standard dose Ir with concurrent Cs (IrCs) ma...

4092 Background: Perioperative chemotherapy is a standard treatment for localised gastric/OGJ adenocarcinoma. B is a monoclonal antibody targeting vascular endothelial growth factor A. Addition of ...

2588 Background: Pre-clinical data demonstrates that Gem and FP treatment leads to substantial falls in MDSCs in murine cancer models. We prospectively evaluated whether such a phenomena occurs in patients (pts) with cancers treated with these agents. Methods: Peripheral blood was collected from pancreatic and esophago-gastric cancer pts prior to and following Gem or FP based therapy. PBMC was harvested with subsequent flow-cytometric analysis of HLADR- Linlow/- CD33+ CD11b+ MDSCs. Percentage change in MDSC value was compared to independent evaluation of tumor volume percentage change, measured using the RECIST v1.1 criteria for target lesion assessment. Results: 16 PC pts receiving Gem based treatment and 23 EGC pts treated with FP based therapy were analyzed. There was a statistically significant reduction in pre and post treatment MDSC % (p 10% decrease in tumor volume, 20 had a fall in MDSCs, 60% of whom the MDSCs fell by >30%. There was a statistically significant red...

4131 Background: EOC is a standard treatment option for advanced OG cancer. Epidermal growth factor receptor (EGFR) overexpression is common in OG cancer and associated with poor prognosis. P is a ...

TPS187 Background: BIBW 2992 is an oral, irreversible inhibitor of EGFR/HER1 and HER2. EGFR and HER2 are amplified and overexpressed in most epithelial cancers as well as 50%–60% of GBMs. In a phase I study, one patient with NSCLC and brain metastases showed a response in both systemic and CNS disease. Preclinical and retrospective ECG analyses did not suggest an effect of BIBW 2992 on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. The primary objectives of this study are to evaluate the effect of BIBW 2992 on QTc interval and the efficacy in patients with GBM, and patients with eligible tumors with and without brain metastases. Methods: In this phase II open label study, patients ≥18 years, with tumors known to historically overexpress EGFR or HER2, including those with brain metastases, and GBM at 1st recurrence, adequate organ function and ECOG PS 0–2, are eligible for treatment with BIBW 2992 50 mg PO OD q28. Patients with a QTcF...

4019 Background: Perioperative chemotherapy is a standard of care for localised oesophagogastric cancer. B is a monoclonal antibody targeting vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis. Tumour VEGF expression and high preoperative serum VEGF are independent predictors of poor prognosis for resected gastric cancer. ST03 is an ongoing randomised phase II/III trial of perioperative ECX ± B in pts with operable gastric or OGJ adenocarcinoma. Methods: Pts receive 3 preoperative and 3 postoperative ECX ± B 7.5 mg/kg, then 6 × maintenance B in the experimental arm only. The Independent Data Monitoring Committee undertook a preplanned review of preliminary safety data relating to preoperative chemotherapy and surgery for the first 104 pts. We present these data here to reassure clinicians and patients involved in the trial. Results: 43 ECX and 42 ECX + B pts have completed preoperative chemotherapy, 38 (88%) and 37 (88%) respectively received all 3 cycles. Of the 10 pts who rece...

4003 Background: EPIC, a multinational phase III clinical trial examined the impact of cetuximab on survival in pretreated EGFR- expressing metastatic colorectal (MCRC) patients (pts). Pts were randomized to either cetuximab 400 mg/m2 followed by 250 mg/m2 weekly and irinotecan 350 mg/m2 q 3 weeks or irinotecan alone. The primary endpoint was overall survival (OS) with quality of life being one of the secondary endpoints. Methods: Health Related Quality of life (HRQoL) of pts in this trial was assessed through the EORTC QLQ-C30 questionnaire, version 3.0. Pts completed the questionnaire pretreatment, every second cycle, and at first follow-up visit. HRQoL was compared between treatment arms using a Wei-Lachin test. Results: Baseline demographics were balanced between the arms. Cetuximab plus irinotecan (n=648) was superior to irinotecan alone (n=650) in progression-free survival (HR 0.69, p No significant financial relationships to disclose.

LBA4017 Background: The aim was to establish the potential use of the third generation platinum compound, oxaliplatin (O) & the oral fluoropyrimidine capecitabine (X) in untreated patients (pts) with advanced OG cancer. Methods: After stratification for PS and extent of disease, pts with histologically confirmed adenocarcinoma, squamous or undifferentiated carcinoma of the oesophagus, oesophago-gastric junction or stomach were randomised, in a 2 x 2 design, to 1 of 4 regimens; epirubicin, cisplatin, fluorouracil (ECF), EOF, ECX or EOX. Doses E 50 mg/m2, C 60 mg/m2 & O 130 mg/m2 IV 3 weekly; F 200 mg/m2 IV daily & X 625 mg/m2 twice daily PO continuously; for 8 cycles. The primary endpoint was overall survival. With 1000 pts (250 per arm) the study had 80% power to demonstrate non-inferiority of X over F and also O over C if the upper limit of the HR 95% CI excluded 1.23 (α = 0.05) in the per protocol population. Analysis was performed using the logrank test and Cox regression analysis. Results: 1002 pts were randomised from 61 centres. Demographics were balanced, 89% were PS 0–1, 77% metastatic, median age 63 (range 22–83), 81% were male and 40% gastric primaries. Histology: adenocarcinoma in 88% and 52% poorly differentiated. 11 pts were ineligible and 27 pts were withdrawn before treatment commenced. Median follow up was 17.1 months and 850 events have occurred. There were no significant differences in response rates comparing ECF to, EOF, ECX and EOX (41%, 42%, 46%, and 48% respectively); grade 3–4 non haematological toxicity 36%, 42%, 33% and 45%; and grade 3–4 neutropaenia 42%, 30% (p = 0.008), 51% (p = 0.043) and 28% (p = 0.001) respectively. Conclusions: Capecitabine may replace 5FU and Oxaliplatin may replace Cisplatin in triplet regimens used for the treatment of advanced OG cancer. [Table: see text] [Table: see text]

3622 Background: Elderly and performance status (PS) 2 patients are perceived to tolerate irinotecan poorly and currently these patients are recommended to have a reduced starting dose (300mg/m2 on...