First-line Treatment Of mCRC Research Articles

Phase II study of S-1, oral leucovorin, oxaliplatin, and bevacizumab combination therapy (SOL+BV; SOLA) in patients with unresectable metastatic colorectal cancer (mCRC).

611 Background: The results from a randomized phase II trial in the first-line treatment of mCRC indicated that SOL regimen (S-1, Oral Leucovorin; LV, and Oxaliplatin) had promising activity with well-tolerated toxicities compared to mFOLFOX6 (Ojima et al, ESMO 2011). The median progression-free survival (PFS) for SOL and mFOLFOX6 was 9.6 and 6.9 months, respectively (HR=0.83). We evaluated the efficacy and safety of adding BV to SOL regimen in this study. Methods: The inclusion criteria were; 1) histologically proven adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment for metastatic disease, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (pts) received S-1 (40-60 mg bid) and LV (25 mg bid) orally for one week and L-OHP (85 mg/m2), and BV (5 mg/kg) on day 1, every 2 weeks. The primary endpoint was the response rate (RR). Results: From October 2009 to April 2010, 31 pts were enrolled, and 29 pts were regarded as the population of full analysis set. Present data included the results of efficacy and safety up to 24 cycles. RR assessed by the independent review committee was 86.2 % (CR: 0 pts, PR: 25 pts), and disease control rate (DCR) was 100%. The median PFS assessed by investigators was 12.5 months, while further follow up is ongoing. One year survival rate was 100%. The incidence of grade 3/4 adverse drug reactions were; neutropenia 16.7%, diarrhea 10.0%, hypertension 16.7%, and sensory neuropathy 53.3%. The median cumulative oxaliplatin dose was 915.0 mg/m2 (range 330-1735 mg/m2). The high prevalence of grade 3 neuropathy seemed due to the prolonged treatment duration. Reasons for discontinuation were progressive disease in 13 pts, and metastatectomy by tumor regression in 6 pts. The resection rate was 17.2 %. Conclusions: SOL+BV showed promising activity with high RR, DCR, PFS and resection rate with well tolerated toxicities in pts with unresectable mCRC. This trial was supported by Taiho Pharmaceutical CO.,LTD. (JAPIC Clinical Trials information Identifier: JapicCTI-090881).

Addition of bevacizumab to first-line FOLFOX4 and overall survival in patients with metastatic colorectal cancer.

610 Background: In our previous report, addition of bevacizumab (BV) to the FOLFOX4 regimen appeared to significantly improve response rate, progression-free survival and overall survival in first-line treatment for patients with metastatic colorectal cancer (mCRC) (Suenaga M, et al. ASCO-GI 2011 [abstr 588]). Update results met median overall survival, and statistical analysis of survival was performed. Methods: An observational cohort study was carried out on all eligible patients scheduled to receive FOLFOX4 (n = 128) or FOLFOX4+BV (n = 85) between 2005 and 2007, 2007 and 2009, with a median follow-up time of 20.4 months vs. 30.2 months, respectively. Predefined efficacy endpoints were treatment characteristics, response rates, progression-free survival, and overall survival in the periods of time observed. Results: Median progression-free survival was 9.9 months (95% CI, 8.4-11.4) in the FOLFOX4- and 17 months (95% CI, 11.8-22.3) in the FOLFOX4+BV-treated patients (p=0.002). Median overall survival times were 20.5 months (95% CI, 16.9-24) and 38.8 months (95% CI, 32.9-44.8) in the two groups, respectively (p<0.001). In the ECOG PS 0 population, progression-free survival in the FOLFOX4 and FOLFOX4+BV groups was 11 months and 17 months with a hazard ratio of 0.63 (95% CI, 0.44-0.89) in favour of FOLFOX4+BV, similarly in OS with a hazard ratio of 0.53 (95% CI, 0.36-0.77). Subgroup population received 5-FU plus leucovorin (FL) as maintenance during oxaliplatin discontinuation due to adverse events had longer PFS or OS in both groups, though no significance. PFS were 14.7 and 21.6 months, and OS were 29 and 45.9 months, respectively. Secondary resection was performed more in FOLFOX4+BV (11.8%) than FOLFOX4 (3.9%) patients. Conclusions: These data indicate potential survival benefits from the addition of BV to the FOLFOX4 regimen as first-line treatment for mCRC. Maintenance using FL after discontinuation of oxaliplatin due to adverse events appeared to be an essential factor for better survival.

Comparison between the three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer.

687 Background: XELOX (capecitabine/L-OHP) therapy that includes orally administered fluoropyrimidine instead of infusional fluorouracil (5-FU) was approved for metastatic colorectal cancer (mCRC) in Sep 2009 in Japan. A pivotal trial (NO16966 study) demonstrated the non-inferiority of XELOX to FOLFOX (5-FU/L-OHP/LV) and the superiority of those L-OHP-based regimens plus bevacizumab (BV) to those without in the first-line treatment of mCRC. We evaluated the safety and efficacy of XELO+BV compared with FOLFOX4 or mFOLFOX6 plus BV in the first-line treatment for mCRC patients at a single institute. Methods: Between Jun 2007 and Nov 2008, 85 patients received FOLFOX4+BV (FF4 arm), between Dec 2008 and Sep 2009, 40 patients received mFOLFOX6+BV (FF6 arm), and between Oct 2009 and Sep 2010, 60 patients received XELOX+BV (XELOX arm). The best overall responses were evaluated using RECIST 1.0 during chemotherapeutic treatment, and adverse events were graded according to CTCAE ver.3.0. Progression-free survival (PFS) was estimated by Kaplan-Meier methods. Results: Characteristics of patients of FF4 arm, FF6 arm, and XELOX arm were below: median age, 60 yr vs. 62 yr vs. 60.5 yr; gender (male), 48.2 % vs. 62.5 % vs. 58.3%. The overall response rates (CR+PR) were 61.1 %, 72.5 %, and 75 % (95% CI; 50.6-71.8%, 58.0-87.0%, and 63.7-86.3%). Median PFS were 17.0 months, 15.5 months, and 14.4 months, respectively (cut-off: Aug 31, 2011). There were no statistical significances not only between FF4 arm and FF6 arm (log-rank; p=0.641), but also between XELOX arm and FF4+FF6 (FOLFOX) arm (log-rank; p=0.138). FOLFOX arm was associated with higher incidence of grade 3/4 neutropenia than XELOX arm. Grade3 diarrhea and hand-foot syndrome (HFS) were more frequent in XELOX arm. Conclusions: This study suggests that XELOX arm was equal to FOLFOX arm, regardless of regimen, in tumor response and PFS. Further follow-up is necessary to confirm the benefit on survival.

A systematic review of treatment guidelines for metastatic colorectal cancer

AimA systematic review of treatment guidelines for metastatic colorectal cancer (mCRC) was performed to assess recommendations for monoclonal antibody therapy in these guidelines.MethodRelevant papers were identified through electronic searches of MEDLINE, MEDLINE In Process, EMBASE and the Cochrane Library; through manual searches of reference lists; and by searching the Internet.ResultsA total of 57 relevant guidelines were identified, 32 through electronic database searches and 25 through the website searches. The majority of guidelines were published between 2004 and 2010. The country publishing the most guidelines was the USA (12), followed by the UK (10), Canada (eight), France (eight), Germany (three), Australia (two), Spain (two) and Italy (one). In addition, eight European and three international guidelines were identified. As monoclonal antibody therapy for mCRC was not introduced until 2004, no firm recommendations for monoclonal antibody therapy were made in guidelines published between 2004 and 2006. Recommendations for monoclonal antibody therapy first appeared in 2007 and evolved as more data became available. The most recent international, European and US guidelines recommend combination chemotherapy with the addition of a monoclonal antibody for the first-line treatment of mCRC. Second-line treatment depends on the first-line regimen used. For chemoresistant mCRC, cetuximab or panitumumab are recommended as monotherapy in patients with wild-type KRAS tumours.ConclusionThe study indicates that recent treatment guidelines have recognized the role of monoclonal antibodies in the management of mCRC, and that treatment guidelines should be updated in a timely manner to reflect the most recently available data.

Phase II study of oral S-1 with irinotecan and bevacizumab (SIRB) as first-line therapy for patients with metastatic colorectal cancer

Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and the progression-free survival was 8.0 months. We report here on an update of efficacy and safety of the SIR plus bevacizumab (SIRB) regimen as first line treatment for mCRC patients. Fifty-one eligible patients with histologically confirmed advanced or recurrent colorectal cancer received this treatment. S-1 was administered orally on days 1-14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg, 50 mg, or 60 mg. Irinotecan (150 mg/m(2)) plus bevacizumab (7.5 mg/kg) were administered by intravenous infusion on day 1. Safety analysis identified a grade 3/4 neutropenia rate of 26%. Other grade 3/4 toxicities were diarrhea (8%), nausea (6%), vomiting (2%), and hypertension (8%). The response rate was 67% and the median progression-free survival time was 373 days. The SIRB regimen appears to be highly active and well tolerated as first-line treatment for mCRC.

A genotype-directed phase I–IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer

Background:Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.Patients and methods:Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m−2 for the *1/*1, 110 mg m−2 for the *1/*28 and 90 mg m−2 for the *28/*28 genotypes.Results:The dose of irinotecan was escalated to 450 mg m−2 in patients with the *1/*1 genotype, to 390 mg m−2 in those with the *1/*28 genotype and to 150 mg m−2 in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.Conclusions:Our results demonstrated that the recommended dose of 180 mg m−2 for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m−2.

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (mCRC): Analysis of patients with KRAS-mutated tumors in the randomized German AIO study KRK-0306.

3575 Background: The German AIO study KRK-0306 is a randomized phase III trial that investigates the efficacy and safety of cetuximab plus FOLFIRI versus bevacizumab plus FOLFIRI in the first-line treatment of mCRC. Until September 2008, patients (pts) without knowledge of their KRAS mutational status had been enrolled. Here, results of the subgroup of pts with mCRC carrying a mutated KRAS gene are presented. Methods: Until September 2008, a total of 336 mCRC pts were randomized to FOLFIRI (irinotecan 180mg/m2, folinic acid 400mg/m2, 5-FU 400mg/m2 bolus application, day 1 followed by continuous infusion of 2,400mg/m2 5-FU over 46h q2w) plus cetuximab (400mg/m2 day 1, followed by 250mg/m2 weekly = arm A) or bevacizumab (5mg/kg q2w = arm B). At the time of analysis, KRAS mutation was documented in 96 pts (ITT population). The primary endpoint of this study was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), rate of secondary liver resections, toxicity and safety. Results: Median follow-up was 20.4 months. In pts assessable for treatment efficacy (on treatment until the first tumor assessment) receiving arm A (n=41) versus arm B (n=46), ORR was 43.9% versus 47.8%. In the ITT population PFS was 7.5 months versus 8.9 months, and OS (56% of events occurred) was 21.1 months versus 16.8 months, respectively, indicating no significant differences between the two treatment arms (HR 1.12). A total of 8 pts (8.3%) reached surgical resectability for metastases. The most common grade 3/4 toxicities (arm A versus arm B) were exanthema (20% versus 0%), hypertension (8% versus 21.7%) and thromboembolic events (10% versus 19.5%). In arm A skin rash grade 1-4 was associated with a trend towards longer PFS (7.6 versus 3.5 months, logrank p=0.108). 60-day mortality rate was 1%. Conclusions: In this analysis of KRAS mutated pts, no significant differences with regard to efficacy could be observed between pts receiving chemotherapy plus cetuximab versus bevacizumab.

Modified FOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC. Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC). Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%). The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer

Background:The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC).Methods:Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: −2578A/C, −1498C/T, −1154A/G, −634C/G and 936C/T; and VEGFR-2: −604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients.Results:Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found.Conclusion:Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.

Cetuximab Plus Capecitabine and Irinotecan Compared With Cetuximab Plus Capecitabine and Oxaliplatin As First-Line Treatment for Patients With Metastatic Colorectal Cancer: AIO KRK-0104—A Randomized Trial of the German AIO CRC Study Group

The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC). A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR). In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe. This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.

Biomolecular, biochemical, and radiologic evaluation of patients on anti-VEGF treatment for mCRC.

556 Background: K-ras mutation is a negative predictor of clinical benefit (CB) from anti-EGFR treatment in mCRC. Bevacizumab combined with chemotherapy prolongs both PFS and OS in first-line treatment of mCRC. Previously data suggested that this results are independent of K-ras status. We conducted a study to investigate the CB of Bevacizumab in treatment of mCRC according to K-ras status and to evaluate timing of response to treatment trough the correlation between tumor markers values and clinical responses. Finally we evaluated CB in patients affected by mCRC with only hepatic metastases vs patients with multiple metastasis sites. Methods: 82 patients were enrolled and underwent first-line chemotherapy with Folfiri or FolFoX and bevacizumab. Tissue samples were analyzed for DNA sequencing in order to identify K-ras mutations in codons 12 and 13. Before therapy all patients were investigated with CT scan and with a blood sample to define tumor markers values; a new evaluation of tumor markers after 2 months of chemotherapy was performed and a CT scan after 3 months. Results: An overall objective response rate (RR) of 40% and a CB of 79% were obtained, with a correlation between tumor markers values and clinical response of 89%. 49% of population presented only hepatic metastases while other 51% showed multiple metastatic sites. RR in exclusive hepatic metastatic group was 45% vs 33% multiple metastatic sites group, CB was 90% vs 66% respectively. No grade 3 or 4 bevacizumab associated toxicity was showed in patients. K-ras mutations were investigated in 75 of 82 patients. 49 patients were wild-type (wt 65%) while 26 patients were mutated (mut 35%). RR in wt group was 45% vs 35% in mut group, while CB was 82% vs 81% respectively. Correlation between tumor markers values and clinical response was 90% in wt group vs 93% in mut group. Conclusions: RR in two K-ras groups was different with an advantage in K-ras wt group, but this difference does not observe in CB. Bevacizumab provides significant RR and CB after a short time of treatment and tumor markers values could be an optimal correlative parameters of early clinical response. Bevacizumab provides significant CB in patients with only hepatic metastases vs patients with multiple metastatic sites. No significant financial relationships to disclose.

MFOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study.

569 Background: In metastatic colorectal cancer (mCRC), a combination of leucovorin and fluorouracil with oxaliplatin (FOLFOX) is one of the standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. The aim of this study was to evaluate modified FOLFOX6 (mFOLFOX6) with the intermittent oxaliplatin treatment and maintenance therapy with S-1, oral fluoropyrimidine derivative, in the first-line treatment of mCRC. Methods: Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 5-fluorouracil continuous 2400 mg/m2, every 2 weeks) followed by maintenance therapy with oral S-1 (S-1 80- 120mg/body days 1-28, every 6 weeks). Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or tumor progression. The primary study end point was duration of disease control (DDC). Results: Twenty of the 30 patients (66.7%) who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in thirteen patients (43.0%). Median DDC was 9.3 months. Median progression-free survival (PFS) was 7.9 months. Overall response rates and disease control rates were 40.0% and 86.6% for the initial mFOLFOX6, 25.0% and 55.0% for S-1 maintenance therapy and 23.1% and 76.9% for mFOLFOX6 reintroduction. Twenty-eight patients (93.3%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.3%). Conclusions: The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible first-line treatment for Japanese mCRC patients. Further prospective randamized control study is warranted. No significant financial relationships to disclose.

Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group.

365 Background: The role of anti-EGFR therapy in first-line treatment of metastatic colorectal cancer (mCRC) is not established. In the present study pts were randomized to FLOX or FLOX + cetuximab until progression or FLOX intermittently + cetuximab continuously. Methods: Treatment arm A: Nordic FLOX (q2w): oxaliplatin 85 mg/m2day 1, 5-FU bolus 500 mg/m2 and FA 60 mg/m2 day 1-2; B: FLOX + cetuximab, initial dose 400 mg/m2, then 250 mg/m2/week; C: FLOX for 16 weeks + cetuximab continuously, with FLOX added at progression. Primary endpoint was progression-free survival (PFS). Results: Between May 05-Oct 07, 571 pts were randomized, 566 pts evaluable in intention to treat (ITT) analyses. Median age was 61 (24-74). ECOG status: 0=67%, 1=29%, 2=4%. KRAS and BRAF mutation (mut) analyses were obtained in 498 (87%) and 457 pts (81%), respectively. 40% of tumors had KRAS mut, 12% had BRAF mut. Cetuximab combined with Nordic FLOX did not significantly improve RR, PFS or OS compared to FLOX. KRAS mutation was not predictive for cetuximab effect. OS was similar for patients treated with FLOX intermittently and cetuximab continuously as for patients treated until progression. BRAF mutation was a strong negative prognostic factor (median OS 7.6 vs. 20.4 mo). Conclusions: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC, irrespective of KRAS-mut. [Table: see text] [Table: see text]

Effect of the addition of bevacizumab to first-line FOLFOX on efficacy, including response rate, progression-free survival, and overall survival, in patients with metastatic colorectal cancer.

588 Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Used in combination with chemotherapy, BV has been shown to improve survival in both first- and second-line treatment for metastatic colorectal cancer (mCRC). However, it was reported that addition of BV to FOLFOX conferred only little survival benefit (Saltz et al. JCO2008). The aim of this study was to assess the efficacy of addition of BV to FOLFOX in first-line treatment for patients with mCRC. Methods: Bevacizumab was approved for mCRC in July 2007 in Japan. This study was conducted at a single institution and comprised 217 consecutive patients receiving first-line treatment for mCRC between 2005 and 2009. The primary objective was to compare survival benefit in patients treated with FOLFOX4 (FF) between 2005 and 2007 with that in patients receiving FOLFOX4+BV 5 mg/kg (FF+BV) between 2007 and 2009. Results: Total number of patients in the FF and FF+BV groups was 132 and 85, respectively. Characteristics of patients were as follows (FF vs. FF+B): median age, 62 yrs (range 28-76 yrs) vs. 60 yrs (range16-74 yrs); ECOG PS0, 98.8% vs. 81.8%; and median follow-up time, 20.8 months vs. 24.4 months. Median progression-free survival (PFS) in the FF and FF+BV groups was 10 months (95% CI, 8.7-11.3) and 17 months (95% CI, 10.2-14.1), while median overall survival (OS) was 21 months (95% CI, 17.9-24.1) and not reached, respectively. Response rate was 46% (95% CI, 37- 54) in FF, and 62% (95% CI, 51-73) in FF+BV. Addition of BV to FOLFOX4 significantly improved PFS (p=0.002) and OS (p<0.001). Conclusions: The additive effect of BV for first-line FOLFOX was reconfirmed. These data indicate potential survival benefits from the addition of BV to FOLFOX in first-line treatment of mCRC. In addition, PFS may be a sensitive indicator of outcome prior to post-treatment. No significant financial relationships to disclose.

A novel low-toxicity regimen for advanced colorectal cancer?

Doublet fluoropyrimidine-based chemotherapy is the standard of care for the first-line treatment of metastatic colorectal cancer (mCRC). However, single fluoropyrimidine-based therapy remains an important alternative. In this article, we highlight the potential impact of a recent trial assessing the addition of bevacizumab to capecitabine in the first-line treatment of mCRC.

Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities.

Optimization of routine KRAS genotyping procedure for rational selection of first-line targeted therapy in metastatic colorectal cancer (mCRC).

e14008 Background: KRAS genotyping represents a first step towards individualized therapy and has become a crucial issue in mCRC. The optimization of KRAS genotyping delay enabling rational prescription of first-line treatment in mCRC including anti-EGFR targeted therapy, requires robust and rapid molecular biology techniques. Methods: Between June 2008 and December 2009, 844 mCRC have been analyzed for KRAS mutations. Following prescription of KRAS genotyping by medical oncologists, the tumor specimens were collected from private and academic pathologists, as paraffin-embedded tissue specimens, and macrodissected after hematoxylin-eosin slide analysis by a pathologist to ensure a minimum of 50% tumor tissue content. DNA was then extracted and controlled. Routine KRAS genotyping, restricted to exon 2 mutations in codon 12 and 13, was performed using three molecular biology techniques i.e. high resolution melting (HRM), PCR-RFLP and allelic discrimination PCR (TaqMan). Results: Among the 844 tumor specimens, 3% (25/844) had excessive DNA degradation and could not be analyzed. KRAS mutations were detected in 41% (334/819) of the analysable specimens with 81% (274/334) of the mutations being located in codon 12 and 19% (60/334) in codon 13. Among 549 specimens in which all three techniques were used, 15 (2.7%) cases of discordance between the three techniques were observed. In these discordant cases, the whole procedure (from DNA extraction) was systematically repeated. 53% of the discordances was due to PCR-RFLP, as revealed by a second analysis of the same sample, 33% to TaqMan, 13% to HRM. From these results, in order to reduce the duration of KRAS genotyping, HRM and TaqMan are used as genotyping techniques and PCR-RFLP only used in cases of discordance, helping to optimize the genotyping delay that is a crucial point for the prescription of first-line treatment in mCRC. Conclusions: The results obtained show an excellent correlation between the three techniques used. Using HRM warrants high quality and rapid routine KRAS genotyping in paraffin-embedded tumor specimens enabling rational prescription of first-line targeted therapy in mCRC. No significant financial relationships to disclose.

Final analysis of the randomized trial of the German AIO CRC study group: Cetuximab plus XELIRI versus cetuximab plus XELOX as first-line treatment for patients with metastatic colorectal cancer (mCRC).

3540 Background: Cetuximab combined with 5-fluorouracil/folinic acid plus irinotecan or oxaliplatin has shown activity in the treatment of mCRC. This randomized phase II trial investigated the efficacy and safety of the epidermal growth factor receptor antibody cetuximab combined with the oral fluoropyrimidine capecitabine plus irinotecan (XELIRI) or oxaliplatin (XELOX) in the first-line treatment of mCRC. Methods: A total of 185 mCRC patients were randomized to cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly) plus XELIRI (irinotecan 200 mg/m2, day 1; capecitabine 800mg/m2; twice daily days 1-14, every 3 weeks; 20% dose reduction of both agents for patients older than 65 years) or cetuximab plus XELOX (oxaliplatin 130 mg/m2 day 1; capecitabine 1,000 mg/m2 twice daily days 1- 14, every three weeks). The primary study endpoint was objective response rate (ORR). KRAS mutation status (wild type or mutant) was determined on codons 12/13 using a mutation-specific quantitative PCR-based assay. Results: In the intention-to-treat patient population (n = 177), ORR was 46.1% (95% CI: 35.4-57) versus 47.7% (95% CI: 37-58.7) and the disease control rate 74.2% versus 77.3% for cetuximab plus XELIRI versus cetuximab plus XELOX. Time to progression and overall survival were 6.3 and 21.1 months for cetuximab and XELIRI compared to 7.7 and 25.5 months for cetuximab and XELOX. Secondary resection was possible in 9.2% of patients with liver metastases. Both study treatments had manageable tolerability profiles and were safe. The most common grade 3/4 toxicities in the cetuximab plus XELIRI arm versus cetuximab plus XELOX arm were diarrhea (15.7% versus 19.3%), cetuximab-induced exanthema (12.4% versus 20.5%), and sensory neurotoxicity (1.1% versus 14.8%). KRAS analysis data will be presented at the meeting. Conclusions: This randomized trial demonstrates the efficacy and tolerability of cetuximab combined with XELIRI or XELOX for the first-line treatment of patients with mCRC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Roche Merck, Pfizer, Roche, sanofi-aventis Merck, Pfizer, Roche, sanofi-aventis

Exploratory analysis of circulating pro- and antiangiogenic factors in metastatic colorectal cancer (mCRC) patients, treated with GONO-FOLFOXIRI plus bevacizumab (BV).

e14094 Background: The combination of the anti-VEGF BV with cytotoxic drugs is an efficacious strategy in the treatment of mCRC. It has been hypothesized that the trend over time of circulating levels of pro- and antiangiogenic factors might help to predict treatment's efficacy and to disclose mechanisms of acquired resistance. Methods: Plasma levels of VEGF, placental growth factor (PIGF), soluble VEGF receptor 2 (sVEGFR2) and thrombospondin-1 (TSP-1) were assessed by means of ELISA assay, in a cohort of 25 patients enrolled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF levels were measured on immunodepleted plasma samples collected at baseline (d1), immediately before the second (d15), the fifth (d57) and the twelfth (d155) cycle of therapy and/or at the time of radiographic progression (PD). PIGF, sVEGFR2 and TSP-1 were assessed on plasma samples, collected at the same time points, except for d15. Comparisons were made by the two-sided, nonparametric Wilcoxon paired test. Results: Treatment with GONO-FOLFOXIRI plus BV produced a reduction in plasma VEGF (d15 vs. d1: p = 0.016). VEGF variation was independent of baseline levels (correlation coefficient: 0,105; p = 0.617). VEGF remained lower than at baseline also at d57 (d57 vs. d1; p = 0.002), at d155 (d155 vs. d1; p = 0.001) and at the time of PD (PD vs. day1: p < 0.0001). PIGF levels increased at d57 (d57 vs. d1: p < 0.001) and at d155 (d155 vs. d1: p = 0.019), compared to baseline; a decrease was observed at the time of PD (PD vs. d155: p = 0.049). sVEGFR2 increased at PD, compared to baseline, with a trend towards significance (PD vs. day1: p = 0.083). TSP-1 significantly increased at the time of PD, compared to d155 (PD vs. d155: p = 0.049). Conclusions: Triplet plus BV modulates circulating angiogenic markers, with a relevant effect on VEGF and PIGF levels. The characterization of the angiogenic profile of each patient at any time point might be a new starting point to better individualize antiangiogenic treatment and to focus on innovative therapeutic targets. At present, the small sample size does not allow correlations with clinical outcome. To this end, wider analyses are currently ongoing. No significant financial relationships to disclose.

First-line bevacizumab (BEV) and chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a developing nation.

e14082 Background: More than 2/3 of the 20 million new cases of cancer predicted to occur yearly by 2020 will be in developing nations. Access to cancer treatment is a major issue in the developing world and evidence-based programs should be used whenever possible. BEV significantly extends overall survival (OS) when added to standard first-line CT for mCRC and although previous observational studies showed that the efficacy and safety profile of BEV in routine practice was consistent with data from phase III trials, no separate results from developing nations were described until now. Here, we report the results of the Bevacizumab Expanded Access Trial (BEAT) in a cohort of Brazilian patients. Methods: Patients with unresectable and previously untreated mCRC received the physician's choice of a fluoropyrimidine-based CT in combination with BEV 5 mg/kg q2w (5- fluorouracil [5-FU] regimens) or 7.5 mg/kg q3w (capecitabine [cap] regimens). Primary objective was safety evaluation, particularly the incidence of adverse events (AEs) related to BEV. Secondary objective was efficacy assessment, including time to progression (TTP), progression free-survival (PFS) and OS. Results: This study enrolled 168 patients from 28 centers in Brazil, from May 2006 to March 2007. Final analysis included 162 patients who received ≥ 1 BEV dose (female 55%; median age 59 years; 30% ≥ 65 years; ECOG PS 0/1 75%/23%). CT regimens most commonly used with BEV included FOLFOX (44%), 5-FU/cap monotherapy (21%) and FOLFIRI (13%). Median follow-up was 17.7 months (range 0.4 to 36.5 months), and 155 patients (95.7%) were followed for > 60 days. Grade 3-4 AEs of special interest included hypertension (3.1%) and proteinuria (2.5%). There were no cases of grade 3-4 bleeding or thromboembolism. Median TTP, PFS and OS were respectively 11.4 months (95% CI: 9.5; 13.9), 11.0 months (95% CI: 9.5; 13.9) and 21.6 months (95% CI: 18.3; 25.5 months). Conclusions: The results observed with the use of BEV in a cohort of mCRC patients from a developing nation were consistent to those obtained in the United States and internationally. These data further support the addition of BEV to CT in the first-line treatment of mCRC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche