Biliary tract cancers (BTC) are rare and often diagnosed in late stages with advanced, nonresectable disease. The targeted agents panitumumab and bevacizumab have shown promising outcomes in combination with chemotherapy in other gastrointestinal (GI) cancers. We wanted to investigate if panitumumab or bevacizumab was the most promising drug to add to chemotherapy. Eighty‐eight patients were randomized to combination chemotherapy supplemented by either panitumumab 6 mg/kg or bevacizumab 10 mg/kg on Day 1 in Arm A and Arm B, respectively. All patients received gemcitabine 1000 mg/m2 on Day 1, oxaliplatin 60 mg/m2 on Day 1 and capecitabine 1000 mg/m2 twice daily from Days 1 to 7. Treatment was repeated every 2 weeks until progression or for a maximum of 6 months. At progression, crossover was made to the other treatment arm. The primary endpoint was progression‐free survival (PFS) at 6 months. With 19 of 45 in Arm A and 23 of 43 in Arm B PFS at 6 months, the primary endpoint was not met. The overall response rate (ORR) was 45% vs 20% (P = .03), median PFS was 6.1 months vs 8.2 months (P = .13) and median overall survival (OS) was 9.5 months vs 12.3 months (P = .47) in Arm A and Arm B, respectively. Our study showed no consistent differences between adding panitumumab or bevacizumab to chemotherapy in nonresectable BTC and none of the two regimens qualify for testing in Phase III. However, we found a higher response rate in the panitumumab arm with potential implication for future trials in the neoadjuvant setting.

Background: Molecular markers may identify subgroups of patients with clinically distinct behavior and response to treatment. In some gastrointestinal tumors, KRAS has prognostic value and negative predictive value. This is the first prospective study to report the outcome of combination chemotherapy in biliary tract cancer patients with KRAS mutation.Methods: From 2009 to 2015, 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, ECOG performance status 0-2 and tumor KRAS mutation. A bi-weekly cycle of chemotherapy was administered as gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1, followed by 7 days of oral capecitabine 1000 mg/m2. Response evaluation was done every six treatment and the primary endpoint was the fraction with progression free survival (PFS) at 6 months. The study also included a non-preplanned analysis of circulating tumor specific DNA.Results: Chemotherapy was given for a median of 5 months (range 0-14) and among 17 patients evaluable for response, best responses were complete response (1), partial response (2), and stable disease (14). Eighteen patients had CT-verified progression, six died between evaluations and one patient is still progression-free. Median PFS was 6.8 months (95% CI 3.1-11.0) and median overall survival (OS) was 11.2 months (95% CI 6.6-14.3). The fraction with PFS at 6 months was 52% (95% CI 31-69%). Exploratory analyses found an improved survival in patients with a low level of plasma DNA.Conclusion: Pretreatment molecular characterization was feasible in BTC, but the rate of KRAS mutations was low. The study met its primary endpoint with a fraction of PFS at six months of 52%. The effect of combination chemotherapy with gemcitabine, oxaliplatin and capecitabine in this selected population was comparable to results from unselected groups with PFS and OS of 6.8 and 11.2 months, respectively. ClinicalTrials.gov NCT00779454.

e15620 Background: KRAS mutations occur in biliary tract cancer (BTC) at a low rate and little is known as to prognosis and response to chemotherapy for this subgroup. This is the first prospective study to report the outcome of combination chemotherapy in BTC patients with a prespecified molecular characteristic of KRAS mutation. The aim was to investigate the feasibility of combination chemotherapy in patients with KRAS mutated BTC. Methods: From 2009 to 2015 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, performance status 0-2 and tumor KRAS mutation. Chemotherapy was given in a two-week cycle with gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1 followed by 7 days of capecitabine 1000 mg/m2 bid. Response evaluation was done every six treatments and the primary endpoint was the fraction of PFS at 6 months. ClinicalTrials.gov NCT00779454. Results: Sixteen females and 9 males were included and the median age was 69 years (range 50-80). Performance status was 0 (n = 7), 1 (n = 11) and 2 (n = 7). Seventeen patients had metastatic disease and 8 had locally advanced disease. Chemotherapy was given for a median of 5 full months (range 0-14). One grade 4 (febrile neutropenia) and 6 grade 3 toxicity (febrile neutropenia, hyperglycemia and urticaria) was observed, while the commonest grade 1-2 toxicities were neurotoxicity, nausea or vomiting. Among 17 patients evaluable for response, 1 complete and 2 partial responses were seen and the rest had stable disease as best response. 18 patients had progression documented with CT-scans, 6 died between planned evaluations and one patient is still alive without progression. Median PFS was 6.8 months (95% CI 3.1-11.0) and median overall survival was 11.2 months (95% CI 6.6-14.3). The fraction of PFS at 6 months was 52% (95% CI 31-69%). Conclusions: Combination chemotherapy was feasible and the results with a PFS and OS of 6.8 and 11.2 months, respectively, point to an effect in patients with KRAS mutation similar to that of unselected patient populations. Clinical trial information: NCT00779454.

FOLFIRI (folinic acid, infusional 5-fluorouracil, and irinotecan) is a recommended first- and second-line chemotherapy backbone in the treatment of metastatic colorectal cancer (mCRC) (National Comprehensive Cancer Network, 2015). Following a recent review by the European Medicines Agency (EMA), both of the epidermal growth factor receptor (EGFR) inhibitors – panitumumab and cetuximab – are now approved in Europe for first-line use in combination with FOLFIRI or FOLFOX (folinic acid, infusional 5-fluorouracil, and oxaliplatin) in patients with RAS wild-type (WT) mCRC. In the first-line setting, EGFR inhibitors were originally indicated in patients with KRAS WT mCRC in combination with either FOLFOX (panitumumab or cetuximab) or FOLFIRI (cetuximab). Subsequently, mutations were identified in KRAS and NRAS in 17% of patients with non-mutated KRAS exon 2 in the phase III PRIME trial of panitumumab + FOLFOX vs FOLFOX alone (Douillard et al, 2013). As a result, EGFR inhibitor use was refined to include only those patients with RAS WT disease. At the same time, studies also identified BRAF as an important negative prognostic – though not predictive – marker for survival in patients with mCRC, regardless of treatment (Phipps et al, 2012; Douillard et al, 2013; Peeters et al, 2013, 2014a, c). Tumour expression of the biomarker amphiregulin (AREG) has also been correlated with survival during anti-EGFR therapy (Jacobs et al, 2009; Loupakis et al, 2014). The improved risk–benefit profile of EGFR inhibitor treatment in patients selected by RAS status was later verified in trials of first- and second-line FOLFOX and FOLFIRI in combination with panitumumab or cetuximab (Douillard et al, 2013; Heinemann et al, 2014a, 2014b; Venook et al, 2014; Bokemeyer et al, 2015; Van Cutsem et al, 2015). Importantly, patients with RAS mutant (MT) tumours showed no improvement in efficacy with the addition of EGFR inhibitor compared with chemotherapy alone. Indeed, there is some evidence that EGFR inhibitors combined with FOLFOX in such patients are detrimental compared with FOLFOX alone (Douillard et al, 2013; Bokemeyer et al, 2015), and EGFR inhibitors should therefore not be given to patients with RAS MT tumours. Panitumumab plus FOLFIRI demonstrated superiority over FOLFIRI alone in a second-line phase II trial that demonstrated improved progression-free survival (PFS) in patients with RAS WT mCRC, although overall survival (OS) was not significantly different in this study (Peeters et al, 2014b). The only published study of first-line panitumumab plus FOLFIRI in mCRC is a single-arm trial that indicated the efficacy and predictable safety profile of the combination in KRAS WT patients (Köhne et al, 2012), although preliminary data have been presented from a phase II study in which panitumumab plus FOLFOX4 or FOLFIRI was evaluated in patients with KRAS WT colorectal cancer and liver-limited disease (Abad et al, 2014). Here, we present a retrospective analysis of this first-line trial of panitumumab plus FOLFIRI, reporting efficacy and safety data for first-line FOLFIRI plus panitumumab according to tumour RAS/BRAF status and AREG levels in patients with mCRC. The study protocol was approved by the relevant independent ethics committees. The study was conducted in accordance with the regulations and guidelines of the International Conference on Harmonisation of Good Clinical Practice. All patients provided signed, informed consent before any study-related procedures were performed. Data were analysed descriptively by tumour RAS/BRAF status. Tumour specimens were assayed for mutations in KRAS exons 3–4, NRAS exons 2–4 and BRAF exon 15 by bidirectional Sanger sequencing. Mutations in KRAS exon 2 were analysed by CE-marked DxS kit. Baseline tumour AREG levels were analysed in the RAS WT and MT populations. Total RNA was extracted from formalin-fixed paraffin-embedded tissue samples and AREG expression levels were analysed by qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays (see Supplementary Material for details). A cutoff point for AREG status was prespecified based on analysis of data from an earlier clinical trial (STEPP) (Lacouture et al, 2010). Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the PFS hazard ratio (HR) with increasing levels of baseline AREG expression. A Gaussian Process (GP) model was used to fit the PH model (Joensuu et al, 2012) using the GPstuff toolkit in MATLAB (Vanhatalo et al, 2013) – details are included in the Supplementary Material. Overall, 38% of patients had KRAS exon 2 mutations, and 10% had RAS mutations beyond KRAS exon 2 (KRAS exon 3 and 4 mutations each in 3% of tumours; NRAS exon 2 and 3 mutations each in 2% of tumours; no tumour was found to carry an NRAS exon 4 mutation). Complete RAS data were available for 143 of 150 patients, of whom 69 (45%) had RAS WT tumours (i.e., WT for exons 2, 3 and 4 of both KRAS and NRAS). BRAF mutations were present in nine patients (6%), all of whom had tumours that were WT for RAS. The DoR analysis included only those patients who experienced a partial or complete response: 40 patients with mCRC WT for both RAS and BRAF, and 30 patients with MT RAS and WT BRAF mCRC (no patient with BRAF MT disease responded to treatment). Median DoR was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) disease (HR, 0.16 (95% confidence interval (CI): 0.07, 0.37)) (Figure 1). Median DpR (n=141) was also significantly greater in patients with RAS WT (59.3% (Q1, Q3: 26.4, 77.0%)) than in those with RAS MT (35.7% (18.8, 62.0%); P=0.0181) disease. Early tumour shrinkage 30% was reported in 49% of patients with RAS WT disease and 37% of those with RAS MT disease (odds ratio, 1.6), while ETS 20% was reported in 74 and 50% of patients, respectively (odds ratio: 2.8). Early tumour shrinkage was associated with longer PFS in the RAS WT vs MT groups (30% cutoff: median 14.3 vs 7.8 months, HR, 0.29; 20% cutoff: 13.3 vs 7.3 months, HR, 0.34). Furthermore, when patient groups were combined (n=135), patients achieving ETS had significantly longer PFS than those not achieving the relevant ETS criteria (ETS 30% vs <30%: median 10.9 vs 7.2 months, HR, 0.45, P=0.0003; ETS 20% vs <20%: 9.1 vs 6.9 months, HR, 0.48, P=0.0005). Metastasis resection rates (n=143) were numerically higher in patients with RAS WT (n=9; 13% (95% CI: 6.1, 23.3)) vs RAS MT mCRC (n=7; 9% (3.9, 18.5)) and were also higher in patients with RAS WT/BRAF WT (n=9; 15% (7.1, 26.6)) vs those with RAS or BRAF MT status (n=7; 8% (3.5, 16.6)). Rates of complete resection were similar across the four groups (RAS WT, n=4, 6% (95% CI: 1.6, 14.2); RAS MT, n=5, 7% (2.2, 15.1); RAS WT/BRAF WT, n=4, 7% (1.9, 16.2); RAS or BRAF MT, n=5, 6% (2.0, 13.5)). Median PFS (n=143) was longer in patients with RAS WT vs MT status (11.2 vs 7.3 months, respectively; HR, 0.37 (95% CI: 0.24, 0.58)) (Figure 2A) and was also longer in patients with RAS WT/BRAF WT vs RAS or BRAF MT mCRC (13.2 vs 6.9 months, respectively; HR, 0.25 (95% CI: 0.15, 0.41)) (Figure 2B). Median TTP (n=143) was longer in patients with RAS WT (13.2 (95% CI: 7.8, 17.0) months) vs MT tumours (7.3 (95% CI: 6.1, 7.6) months) and in those with RAS WT/BRAF WT (13.3 (95% CI: 9.0, 17.0) months) vs RAS or BRAF MT tumours (7.2 (95% CI: 5.7, 7.4) months). Median overall survival (n=143) was not reached in any of the four RAS/BRAF groups, although the number of deaths was numerically lower in the RAS WT (n=5; 7%) and RAS WT/BRAF WT (n=4; 7%) groups vs the RAS MT (n=11; 15%) and RAS or BRAF MT (n=12; 14%) groups (Cox proportional HR, RAS WT vs RAS MT=0.42 (95% CI: 0.15, 1.23); RAS WT/BRAF WT vs RAS or BRAF MT=0.37 (95% CI: 0.12, 1.15)). The incidence of AEs was similar regardless of tumour RAS/BRAF status (Table 3), and no new safety signals were noted in these analyses. AEs leading to study discontinuation occurred in 24–32% of patients across RAS/BRAF groups (Table 3), and treatment-related AEs leading to study discontinuation occurred in 16–27% of patients across RAS/BRAF groups (Table 3). Skin toxicity of any grade occurred in 68 of 69 patients (99%) with RAS WT tumours, 71 of 74 patients (96%) with RAS MT tumours, 59 of 60 patients (98%) with RAS WT/BRAF WT tumours and 80 of 83 patients (96%) with RAS or BRAF MT tumours. The Cox PH model showed a significant RAS-by-AREG interaction (P=0.03) (Supplementary Table S4). There was a steep transition between responders and non-responders as AREG expression decreased, which was mainly the result of changes in the RAS WT group (Supplementary Figure S2). This analysis represents the first reported RAS data beyond KRAS exon 2 for panitumumab + FOLFIRI in the first-line treatment of mCRC, an indication that has recently been approved by the EMA. The results show consistently favourable efficacy for first-line panitumumab + FOLFIRI treatment in patients with RAS WT/BRAF WT tumours compared with MT mCRC tumours. This is consistent with the primary data for the KRAS analysis of this study (Köhne et al, 2012), in which response rates for patients with KRAS WT (n=86) and KRAS MT (n=68) tumours were 56 and 38% and median PFS was 8.9 and 7.2 months, respectively. In the current analysis, extended RAS testing identified 69 patients with RAS WT tumours, and small increases in response rate (59%) and median PFS (11.2 months) were seen in these patients compared with the primary analysis population. The results are also consistent with previous RAS analysis data for panitumumab plus FOLFIRI in the treatment of mCRC (Cohn et al, 2011; Mitchell et al, 2011; Peeters et al, 2014b; Abad et al, 2014). Thus, patients whose tumours harbour RAS mutations beyond KRAS exon 2 are unlikely to benefit from addition of panitumumab to FOLFIRI. Consistent results have also been reported in studies with another anti-EFGR monoclonal antibody, cetuximab (Van Cutsem et al, 2015; Heinemann et al, 2014a, b), highlighting the importance of up-front tumour RAS testing in patients being considered for EGFR inhibitor therapy. As OS was neither an end point nor followed in this trial, efficacy of panitumumab + FOLFIRI was consistent with that reported for RAS WT populations in first-line studies of panitumumab + FOLFOX4 (Douillard et al, 2013; Schwartzberg et al, 2014; Douillard et al, 2015), as well as in studies of cetuximab in combination with FOLFIRI or FOLFOX4 (Van Cutsem et al, 2015; Bokemeyer et al, 2011; Ciardiello et al, 2014). For example, in the CRYSTAL study of FOLFIRI plus cetuximab, the PFS in patients with WT RAS (11.4 months) and MT RAS (7.4 months) (Van Cutsem et al, 2015) was almost identical to that in the present study (11.2 and 7.3 months, respectively). The results of the present study are also consistent with previous data showing that BRAF mutations are associated with poor prognosis in mCRC regardless of first-line treatment (Phipps et al, 2012; Morris et al, 2014). Discussion is ongoing, however, regarding the potential usefulness of EGFR inhibitors in patients with RAS WT/BRAF MT mCRC, Two recent meta-analyses, have reached differing conclusions regarding the predictive role of BRAF mutations in patients receiving EGFR inhibitor therapy. While Pietrantonio et al (2015) focus on the lack of significant ORR, PFS or OS benefits on addition of EGFR inhibitors to chemotherapy, Rowland et al (2015), who included trials of first- and second-line treatment, conclude that there is insufficient evidence to demonstrate a different treatment benefit between patients with RAS WT/BRAF WT and RAS WT/BRAF MT disease, and therefore insufficient data to exclude patients with RAS WT/BRAF MT from EGFR inhibitor therapy. Regardless, such patients should therefore be considered to be at high risk of rapid progression and should be managed accordingly. No new safety signals were seen with the combination of panitumumab + FOLFIRI in RAS WT/BRAF WT population; AEs were similar to those seen in the KRAS exon 2 WT population of this study (Thaler et al, 2012) and in previous studies using this combination in patients with mCRC (Cohn et al, 2011; Mitchell et al, 2011; Peeters et al, 2014b). Overall 28% of patients withdrew from study treatment because of AEs. Consistent with existing data on EGFR inhibitors, there was a high incidence of skin toxicity. While there was no protocol-mandated proactive management of skin toxicity in the present study, it is now recommended for patients receiving EGFR inhibitors (Boone et al, 2007; Melosky et al, 2009). An earlier analysis of data from the present study showed a higher incidence of skin toxicity in patients with KRAS WT tumours than in those with KRAS MT tumours (Thaler et al, 2012), which may reflect the higher mean cumulative panitumumab dose and longer duration of treatment (i.e., panitumumab cycles) received by the KRAS WT group. However, exposure-adjusted AE rates showed integument-related toxicity overall to be higher in the KRAS MT vs WT population. Thus there is no evidence of an association between tumour KRAS/RAS status and toxicity. Furthermore, despite the high incidence of skin toxicity, generic quality of life (QoL) instruments have shown no impact of EGFR inhibitors plus FOLFIRI on overall QoL (Melosky et al, 2009; Bennett et al, 2011; Thaler et al, 2012). Although proactive management of skin toxicity may have reduced the impact for patients, it may also be that the QoL tools used in the study provided too general an assessment to determine the true impact of this AE. Future trials of EGFR inhibitors should include skin-toxicity specific QoL assessment tools to support better understanding of the true impact of this AE on patient wellbeing. Among patients with RAS WT mCRC, high AREG expression was associated with response to panitumumab + FOLFIRI. Consistent with other studies (Jacobs et al, 2009; Baker et al, 2011; Pentheroudakis et al, 2013; Loupakis et al, 2014; Jonker et al, 2014; Stahler et al, 2016), there was an interaction between RAS and AREG levels. A higher percentage of patients with RAS WT mCRC had high AREG levels compared with those with RAS MT mCRC, suggesting that AREG levels are associated with EGFR signalling. Further studies are needed to determine whether there is an AREG expression level below which there is little or no response to panitumumab + FOLFIRI treatment. Biomarker studies remain critical to our understanding of targeted agents in mCRC, and warrant further investigation. One of the strengths of this comprehensive study was the high percentage of patients from the original cohort who were available for RAS/BRAF testing – which was conducted centrally for all specimens – allowing the identification of additional risks for lack of response to treatment. It should be noted that the analyses were retrospective and exploratory in nature, although, as noted above, the results were consistent with previous analyses of efficacy by RAS mutation status in patients with mCRC. In conclusion, first-line panitumumab + FOLFIRI was associated with consistently favourable efficacy in patients with RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated, despite the expected high incidence of skin toxicity. The combination of first-line panitumumab + FOLFIRI also gave efficacy similar to that seen in the RAS WT populations in other first-line studies of EGFR-targeted agents plus FOLFIRI or FOLFOX. As per the licensed indication for panitumumab, therefore, patients with RAS mutations should not receive panitumumab treatment. Across all lines of therapy, determination of tumour RAS status improves identification of patients unlikely to respond to treatment with panitumumab compared with evaluation of KRAS exon 2 alone. The combination of panitumumab with FOLFIRI can be considered as an important treatment option for first-line patients with RAS WT/BRAF WT mCRC. MK is an advisor for, and has received honoraria from, Amgen Ltd. R-DH has received honoraria from Amgen Ltd. LM is an advisor for, and has received honoraria and research funding from, Amgen. HL has acted as a consultant/advisor for Amgen Ltd & Roche Ltd. RG has received research support from Amgen. JT has received honoraria and research funding from Amgen Ltd. KSO is a former employee of Amgen Inc. MB, BT, YZ, GD are employees of Amgen Inc. C-HK has acted as a consultant/advisor to Amgen Ltd, Merck KG Darmstadt & Roche Ltd. EF declares no conflict of interest. This work was supported by Amgen (Europe) GmbH. Medical writing support (funded by Amgen (Europe) GmbH) was provided by Dan Booth PhD (Bioscript Medical Ltd). Supplementary Information accompanies this paper on British Journal of Cancer website

BACKGROUND:Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap).PATIENTS AND METHODS:Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed.RESULTS:We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C).CONCLUSIONS:Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results.CLINICALTRIALSGOV:NCT01229813.

4071 Background: Non-resectable biliary tract cancer (BTC) is chemosensitive but there are no clear signals of effect from inhibiting any specific molecular target. The most promising targets are EGFR and VEGF. This trial evaluated the effect of adding panitumumab or bevacizumab to chemotherapy in a crossover design. Methods: Eligible patients with biopsy proven non-resectable BTC, 18+ years (y), KRAS wild-type and performance status (PS) 0-2 were randomized 1:1. Patients in arm A received panitumumab 6 mg/kg + gemcitabine 1,000 mg/m2 + oxaliplatin 60 mg/m2 on day 1 and capecitabine 1,000 mg/m2 b.i.d. on days 1-7 of a 2 weeks cycle. In arm B the chemotherapy was similar but added bevacizumab 10 mg/kg on day 1. At progression patients crossed over to bevacizumab in arm A and to panitumumab in arm B with the same chemotherapy backbone. The primary endpoint was the fraction of patients with PFS at six months (PFS6m). Secondary endpoints were PFS and overall response rate (ORR) both before/after crossover, overall survival (OS), toxicity, translational analysis and of second line treatment. Results: Three centres recruited 88 patients with a median age of 66 y (range 35-84). Selected base line characteristics were PS 0 (n = 23), 1 (n = 47), 2 (n = 18) and 73 metastatic/15 locally-advanced disease. Cases of grade > 2 toxicity were equal with more skin toxicity in arm A and more hypertension and infection in arm B. PFS6m in arm A/panitumumab was 43% (95%CI 29-58) and in arm B/bevacizumab 55% (95%CI 40-70). ORR was 46% (95%CI 30-62) in arm A and 18% (95%CI 6-31) in arm B. Median PFS was 6.1 m (95%CI 5.8-8.1) vs 8.2 m (95%CI 5.3-10.6) and OS 9.5 m (95%CI 8.3-13.3) vs 12.3 m (95%CI 8.8-13.3) in arm A vs B. OS was 17.7, 9.5 and 5.6 m in PS 0, 1 and 2, respectively. As a phase II study, comparisons between treatment arms were exploratory and revealed no differences in PFS6m (p = 0.39), median PFS (p = 0.13) or OS (p = 0.47), but ORR was superior in arm A (p = 0.01). Conclusion: Signals of clinical benefit with respect to PFS and OS were equal for targeting EGFR and VEGF, but ORR was higher with EGFR inhibition. This might have implications for potentially resectable disease in the neoadjuvant setting. Clinical trial information: NCT01206049.

BACKGROUND:To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC).METHODS:154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression.RESULTS:Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression.CONCLUSIONS:First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated.

M. A. Socinski1, I. Okamoto2, J. K. Hon3, V. Hirsh4, S. R. Dakhil5, R. D. Page6, J. Orsini7, N. Yamamoto8, H. Zhang9 & M. F. Renschler9 Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, USA; Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Japan; Stem Cell Transplant Program, Clearview Cancer Institute, Huntsville, USA; Department of Oncology, McGill University, Montreal, Canada; Cancer Center of Kansas, Wichita; The Center for Cancer and Blood Disorders, Fort Worth; Essex Oncology of New Jersey, Belleville, USA; Shizuoka Cancer Center, Shizuoka, Japan; Medical Affairs, Celgene, Summit, USA

BACKGROUND:Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with low-dose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity.METHODS:BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatment-naive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade ≥3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade ≥3 AEs and bevacizumab/IFN-related grade 1-2 AEs occurring from first administration until 28 days after last treatment were reported.RESULTS:A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade ≥3 IFN-associated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7-18.0] and 30.7 months (95% CI: 25.7-not reached), respectively. The ORR was 28.8%.CONCLUSIONS:Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757].

BACKGROUND The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER NCT00598156.

Purpose Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.Methods In this phase II, single-arm study, panitumumab (6 mg/kg) and FOLFIRI [irinotecan (180 mg/m(2)) and leucovorin (400 mg/m(2)) followed by a 5-fluorouracil 400 mg/m(2) bolus and a 2,400-3,000 mg/m(2) continuous infusion] were administered every 14 days until progression. Data were analysed descriptively overall and by tumour KRAS status.Results KRAS data were available for 145/154 (94%) patients: 59% KRAS WT and 41% mutant (MT); mean follow-up was 39.5 versus 35.8 weeks, respectively. Objective responses occurred in 49% of patients: 56% versus 38% in the KRAS WT versus MT groups [(18% difference (95% CI 1-35%); odds ratio 2.1 (95% CI 1.0-4.4)]; median duration of response was 13.0 versus 7.4 months. More patients in the WT group underwent R0 resection (8% vs. 5%); median progression-free survival also favoured this group (8.9 vs. 7.2 months). The most common adverse events (any grade) were integument toxicities (98%), diarrhoea (79%) and stomatitis/oral mucositis (51%).Conclusions As expected, consistently favourable efficacy was observed in patients with KRAS WT versus MT tumours receiving first-line panitumumab plus FOLFIRI treatment.

Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial.

3634 Background: Study 314 was a phase II, single-arm, multicenter study designed to assess the efficacy/safety by KRAS tumor status of first-line pmab plus FOLFIRI in pts with mCRC. Here, we investigate the relationship between QoL and tumor response. Methods: Pmab (6mg/kg) and FOLFIRI were administered every 14 days until disease progression, consent withdrawal, or unacceptable toxicity. EUROQOL EQ-5D Index scores were recorded at screening, every 8 wks until wk 32, every 3 months thereafter until disease progression, and 56 days after stopping study treatment (safety follow up visit). EQ-5D scores range from –0.594 to 1 (1=perfect health). A change of ≥0.08 may be considered clinically meaningful. Data were analyzed descriptively by tumor KRAS status (wild type [WT] or mutant [MT]) and by best overall response. Results: A trend for better tumor response in pts with higher baseline EQ-5D scores was observed. In pts who achieved CR/PR, the difference in EQ-5D score between the WT group and the MT group exceeded the clinically meaningful threshold at wks 8 and 24. Conclusions: Patients with WT KRAS mCRC who respond to panitumumab appear to maintain their EQ-5D score over time. The relationship between QoL and tumor response in this treatment setting should be evaluated in a larger patient population. Change in EQ-5D score from baseline. CR or PR SD PD WT MT WT MT WT MT Mean (SE) baseline score n 45 22 25 26 4 3 0.812 (0.034) 0.817 (0.052) 0.833 (0.039) 0.790 (0.034) 0.720 (0.178) 0.588 (0.205) Mean (SE) change from baseline Wk 8 n 43 21 23 23 3 2 +0.049 (0.032) –0.036 (0.052) –0.023 (0.044) +0.015 (0.030) +0.047 (0.047) –0.087 (0.122) Wk 16 n 39 22 20 19 1 1 +0.067 (0.031) +0.018 (0.045) +0.024 (0.039) –0.007 (0.073) –0.240 (–) –0.327 (–) Wk 24 n 33 19 10 9 1 0 +0.053 (0.028) –0.027 (0.033) +0.014 (0.073) +0.111 (0.046) 0.000 – Wk 32 n 15 8 3 5 1 0 +0.019 (0.037) –0.015 (0.080) +0.195 (0.195) +0.172 (0.081) –0.311 (–) – Safety follow-up visit n 19 14 13 15 2 1 +0.048 (0.042) –0.019 (0.038) –0.040 (0.060) –0.034 (0.085) –0.087 (0.343) +0.000 (–) Abbreviations: CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; SE, standard error.

4546 Background: The phase III AVOREN trial showed that first-line BEV + IFN (9 MIU 3 x weekly [t.i.w]) is effective in pts with mRCC. In a retrospective analysis, efficacy was maintained and IFN-related toxicity improved if IFN dose was reduced to 6 or 3 MIU due to IFN-related toxicity. BEVLiN is the first trial to prospectively assess the safety and efficacy of BEV with low-dose IFN (3 MIU) in mRCC. Methods: 147 nephrectomised pts with previously untreated clear cell mRCC (Motzer score favourable/intermediate) were enrolled (Dec 2008–Feb 2010) into this open-label, single arm, multinational phase II trial. Pts received BEV 10mg/kg q2w + IFN 3 MIU t.i.w until disease progression. Primary endpoints are safety (specific IFN-associated adverse events [AEs] of grade (Gr) ≥3) and progression-free survival (PFS); secondary endpoints are overall survival (OS), overall response rate (ORR) and any Gr ≥3, overall and serious AEs. BEVLiN was designed to allow a cross-trial, descriptive comparison with an AVOREN subgroup (BEV + IFN 9 MIU, pts with favourable/intermediate Motzer score). Initial data cutoff was 20 August 2010 (median follow-up 10.5 months); more mature data will be available in March 2011. Results: BEVLiN baseline pts characteristics are similar to AVOREN BEV + IFN favourable/intermediate Motzer score pts. Median PFS in BEVLiN is 15.6 months (95% CI: 10.1; not reached) versus 10.5 months (95% CI: 10.1; 12.9) in AVOREN subgroup. ORR is 22% in BEVLiN. Incidences of any Gr and Gr ≥3 specific IFN-associated AEs in BEVLiN were lower than in AVOREN subgroup (Table). Conclusions: Incidence of IFN-associated AEs appears reduced with low-dose IFN + BEV without compromising PFS in BEVLiN, compared with a historical control subgroup in AVOREN (15.6 vs 10.5 months, respectively). Protocol predefined IFN-associated AEs. BEVLiN N=146* AVOREN subgroup N=283* AE, % (95% CI) Any Gr Gr ≥3 Any Gr Gr ≥3 Pyrexia 19 (13–27) <1 (<1–4) 45 (39–51) 2 (<1–4) Fatigue 27 (20–35) 4 (2–9) 35 (29–40) 12 (8–16) Asthenia 8 (4–13) 3 (<1–7) 31 (25–36) 9 (6–13) Influenza-like illness 4 (2–9) 0 (0–2) 27 (21–32) 2 (<1–5) Malaise 0 (0–2) 0 (0–2) 3 (1–5) <1 (<1–2) * Treated pts.

BACKGROUND:The optimal chemotherapy in patients with advanced gastric carcinoma (GC) is yet to be determined. We compared sequential administration of docetaxel and irinotecan, both in combination with infused 5-fluorouracil/leucovorin (5-Fu/Lv), and randomly assigned patients to start with either of the two.METHODS:Patients with previously untreated locally advanced or metastatic GC and with measurable lesions (response evaluation criteria in solid tumors; RECIST) were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus/44-h infusion of 5-Fu/Lv (day 1 every 2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses.RESULTS:Eighty-one patients were randomized and 78 started treatment. Complete and partial responses were seen in 31 (40%) patients after 8 weeks and in 32 (41%) after 16 weeks, with similar results in both study arms. The median overall survival (OS) was 11.5 and 10.6 months in arms T and C, respectively (P = 0.3). The two schedules were feasible and did not differ in the overall rate of severe adverse events (SAEs).CONCLUSION:This is the first randomized comparison of two of the newer cytostatic drugs in GC therapy. No differences favoring either arm T or arm C were found with respect to response rate, OS, or toxicity. The median OS of 11 months indicates that sequential administration of the two combinations is effective and is similar to triple combinations. Thus, comparable efficacy to platinum combinations appears to be obtained with newer, less toxic regimens when given sequentially.