KRAS Wild-type mCRC Research Articles

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

BackgroundRetrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. Patients and MethodsOriginally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). ResultsA total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. ConclusionAlthough prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

A phase II trial of panitumumab with irinotecan and S-1 (IRIS) as second-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

732 Background: Panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in second-line chemotherapy increased objective response rate and prolonged progression-free survival (PFS) versus FOLFIRI alone in patients with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) (Peeters et al, J Clin Oncol 2010). This trial (UMIN000004659) evaluated tolerability and efficacy of combination therapy with irinotecan and S-1, an oral fluoropyrimidine (IRIS) plus panitumumab as second-line chemotherapy in patients with WT KRASmCRC. Methods: Main inclusion criteria were: patients with WT KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥20 years. Patients received panitumumab (6 mg/m2) and irinotecan (100 mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was completion rate of protocol therapy (CRT). The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-seven patients were enrolled in 9 centers. The overall CRT was 62.2% (23/37). Most frequent grade 3/4 toxicities were: skin rash (24%), diarrhea (16%), and appetite loss (11%). The overall RR was 32.4% (12/37). Of these, four patients underwent conversion surgery. Median PFS and OS were 9.5 months (95% CI: 3.5-15.4 months) and 20.1 months (95% CI: 16.7-23.2 months), respectively. Conclusions: IRIS plus panitumumab has acceptable toxicity profile and promising efficacy in patients with previously treated WT KRAS mCRC. This regimen can be an additional treatment option for second-line chemotherapy in WT KRAS mCRC. Clinical trial information: UMIN000004659.

Phase II trial of irinotecan plus s-1 (IRIS) with cetuximab (IRIS/Cet) as second-line treatment in patients with KRAS wild-type metastatic colorectal cancer (mCRC): HGCSG0902—Comparison of administration interval in cetuximab treatment.

746 Background: HGCSG0902 is the multicenter phase II study to investigate the safety and efficacy of IRIS/Cet as second-line treatment in patients with KRAS wild type mCRC. RR was 33.3% (95% CI, 20.8%-45.9%), therefore primary endpoint was met (Muto et al. ESMO 2014 ). Here we report an exploratory analysis of outcomes based on administration interval of Cet (every week [EW] vs bi-weekly [BW]). Methods: Eligibility includes histologically confirmed colorectal cancer, previously received oxaliplatin-contained chemotherapy, PS: 0-1, EGFR positive and KRAS WT. Pts. received S-1 80-120 mg/day p.o. on days 1-14 and irinotecan 100 mg/m2 on days 1 and 15 repeated every 28 days. Cet was administrated 400 mg/m2 as loading dose and continued 250 mg/m2 every week or 500 mg/m2 bi-weekly. The primary endpoint was RR and the secondary endpoints were disease control rate, PFS, OS and safety. To compare with EW and BW, Fisher’s exact test was used in terms of patient characteristics, AE, RR, and Log-rank test was used in terms of PFS, OS, and TTF. Results: Between March 2010 and September 2013, 58 pts were enrolled. One patient was not administered (57 pts were safety analysis set), and 3 pts were ineligible (54 pts were efficacy analysis set). Based on each physician choice, 34 pts. of EW and 23 of BW were included in the full safety analysis set. RR was 34.4% in the EW group and 31.8% in the BW group (p=1.000). Median PFS was 4.2 months (95% CI 3.5−4.9) in the EW group and 6.1 months (4.1-8.1) in the BW group (HR 0.752, 95% CI 0.413−1.372, p=0.350). The most common non-hematological adverse events of grade 3 or higher were diarrhea (23.5% in the EW group vs. 52.2% in the BW group: p=0.005) and stomatitis (2.9% in the EW group vs. 30.4% in the BW group: p=0.046), these were significantly more common in the BW group. Conclusions: IRIS/Cet appeared to be highly effective with RR and PFS in the both treatment schedule, and also had met the primary endpoint. Diarrhea and stomatitis were significantly more common in the BW group. Therefore, in case of treatment with IRIS, cetuximab should be administered weekly. Clinical trial information: 000004882.

Exploratory RAS analysis of the phase Ib/II 20060447 trial of rilotumumab (R) or ganitumab (G) plus panitumumab (pmab) versus pmab alone in patients (pts) with previously treated metastatic colorectal cancer (mCRC).

694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evaluable for RAS. Of 92 evaluable pts, 79 (86%) were WT RAS (WT in KRAS and NRAS exons 2, 3, and 4) and 13 (14%) had RAS mutations beyond KRAS exon 2 (mutant in any KRAS exon 3 or 4 or NRAS exon 2, 3, or 4). None of the pts with RAS mutations had an objective response (Table). Of 93 pts evaluable for BRAF, 7 (8%) had V600E mutations (all 7 were WT RAS). Two pts with BRAF V600E tumors had a partial response and were in the pmab+R arm (n=3). No new safety signals were identified. Conclusions: In this small, retrospective study, ORR, PFS and OS were similar between the arms of R or G plus pmab vs pmab alone in pts with WT RAS mCRC tumors. Our findings indicate that RAS mutations beyond KRAS exon 2 impact ORR, PFS, and OS. Clinical trial information: NCT00788957. [Table: see text]

Influence of adjuvant pretreatment on outcome of FIRE-3 (AIO KRK-0306): A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

515 Background: The FIRE-3 study (AIO KRK-0306) was designed to compare the efficacy of FOLFIRI + cetuximab (cet) to FOLFIRI + bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI + bev. Overall survival (OS) was significantly longer in the FOLFIRI + cet arm. Methods: In an exploratory subgroup analysis, patients pretreated with adjuvant chemotherapy were analyzed by Fisher's exact and log rank-test according to tumor response (ORR) and survival data. Patients of the ITT (n=592) and the final RAS wild-type population (n=400) were investigated. Results: See table. Conclusions: Results in patients treated with any adjuvant chemotherapy mirrored those in the whole study population. In adjuvant pretreated RASwt patients a significantly higher ORR was reached in the cet arm when compared to the bev arm (p=0.01). The role of adjuvant treatment on efficacy of first-line therapy remains to be further evaluated. Clinical trial information: NCT00433927. [Table: see text] [Table: see text]

Is panitumumab monotherapy safe in metastatic colorectal cancer patients over 70 years old?

714 Background: Metastatic Colorectal Cancer (mCRC) often occurs in patients older than 70 years old. Monoclonal antibodies targeting EGFR have improved the outcome of mCRC patients. Panitumumab in monotherapy is indicated in wild-type K-RAS mCRC progressing disease following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. Very few data are available in elderly patients receiving panitumumab. Methods: Based on the cohort of the Observatory of Cancer B PL in France, we studied the efficacy and tolerance of panitumumab. We retrospectively collected data from patients treated between July 2008 and January 2014 and older than age 70 and compared the results between two cohorts: one contained patients ages 70 to 74; the other contained patients age 75 and older. Results: 136 patients were identified. The median age was 77. The median number of course received was 7 infusions. There was no difference in outcomes between the patients of the two cohorts. Median overall survival was 6.16 months. Median PFS was 13 weeks. The older patients received less previous chemotherapy ligns than the younger with a statistical difference (p=0.023). Tolerance was acceptable with a skin toxicity rate of 67% and 11.5% of grade 3-4. No diarrhea or hypomagnesemia were reported. Conclusions: Our study shows that panitumumab is feasible in elderly patients "in the real world" and has comparable efficacy than in younger patients.

Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial

BackgroundIntegrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). MethodsEligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500mg (arm A) or 1000mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. ResultsPhase I showed that abituzumab doses up to 1000mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78–1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77–1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54–1.28); arm B versus SoC, HR 0.80 (95% CI 0.52–1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A [HR 0.55 (0.30–1.00)] and B [HR 0.41 (0.21–0.81)] than in arm C. ConclusionThe primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. ClinicalTrials.gov identifierNCT01008475

Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.

KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRASG12V into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRASG12V overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC.

Anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer: a meta-analysis.

To investigate the correlation between Kirsten rat sarcoma viral oncogene homolog (KRAS) status and the therapeutic effects of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). Randomized controlled trials (RCTs) were identified and the association between KRAS mutation and clinical outcome in mCRC patients treated with anti-EGFR MoAbs was investigated. Ten RCTs were included in this meta-analysis. Progression-free survival and overall survival were used to assess the strength of the relationship between KRAS mutation and clinical outcome. In first-line treatment, survival benefit was confined to patients with wild-type KRAS. Chemotherapy regimens and angiogenesis inhibitor treatment influenced the results of the analysis. Wild-type KRAS mCRC patients did not seem to benefit from oxaliplatin-based chemotherapy (PFS: HR = 0.88, 95%CI: 0.70-1.10; OS: HR = 0.93, 95%CI: 0.82-1.04). Clinical benefit in mCRC patients was limited to therapeutic regimens which included anti-EGFR MoAbs and fluorouracil-based therapy (PFS: HR = 0.77, 95%CI: 0.69-0.86; OS: HR = 0.85, 95%CI: 0.75-0.95). When anti-EGFR MoAbs were used as second- or further-line treatment, clinical benefit was still confined to patients with wild-type KRAS. KRAS status is a potential predictive marker of clinical benefit due to anti-EGFR MoAb therapy in mCRC patients.

A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer

PurposeThis randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated. Patients and methodsPatients with KRAS wild-type tumours were randomised 2:1 to afatinib (40mg/day, increasing to 50mg/day if minimal toxicity) or cetuximab weekly (400mg/m2 loading dose, then 250mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS). ResultsPatients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5days for afatinib and cetuximab, respectively. Median OS was 355days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups. ConclusionsThe efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.

IS7-3 - Current Status and Future Perspective of Therapeutic Strategy for Metastatic Colorectal Cancer in Japan

In the last decade, unprecedented advances have been seen in the treatment of metastatic colorectal cancer (mCRC). Clinical developments of new active agents such as irinotecan, oxaliplatin, bevacizumab, cetuximab and panitumumab have contributed to this great progress in the prognosis of mCRC. Recently, a multikinase inhibitor called regorafenib showed survival benefits for patients with mCRC who are refractory to all standard therapies. Also, a novel oral nucleoside antitumor agent known as TAS-102 showed promising efficacy in the same population. Therefore, there is current positive development of various new drugs. On the other hand, the development of many active agents and combination chemotherapies has caused the treatment strategy for mCRC to be complicated. So it is necessary to settle clinical questions in order to optimize this complex treatment strategy. With regard to first line chemotherapy, two major clinical questions remain. The first question is whether bevacizumab or anti-EGFR antibodies are more effective for patients with previously untreated KRAS wild-type mCRC. Last year, the PEAK and FIRE-3 studies showed promising survival benefits for anti-EGFR antibody-containing chemotherapy compared with bevacizumab-containing chemotherapy, and the result of the CALGB80405 trial will be presented at the ASCO annual meeting this year. The second question is whether oxaliplatin or irinotecan-based chemotherapy is more suitable for molecular targeting agents. The West Japan Oncology Group conducted a randomized, open-label, phase III trial (4407G study) to assess the non-inferiority of FOLFIRI + bevacizumab to mFOLFOX6 + bevacizumab in progression-free survival. In this session, I would like to introduce the result of the WJOG4407G study and discuss the future perspective of treatment strategy for mCRC.

A Phase 3 Open-Label, Randomized, Multicenter Study of Imprime Pgg in Combination with Cetuximab in Patients with Kras Wild Type Metastatic Colorectal Cancer

ABSTRACT Background: For patients (pts) with epidermal growth factor receptor (EGFR) expressing, KRAS wild-type (WT) metastatic colorectal cancer (mCRC) who failed oxaliplatin- and irinotecan-based therapy or who are intolerant to irinotecan, single-agent cetuximab has been shown to improve objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The mechanism of action of cetuximab is thought to rely on competitive blockade of endogenous ligand binding and downstream signaling, internalization and downregulation of EGFR, as well as antibody-dependent cellular cytotoxicity (ADCC) (Erbitux SmPC). Imprime PGG (Imprime) is a novel immune modulator (complex carbohydrate biologic), which harnesses innate immune cells to enhance killing of antibody-targeted tumor cells. In a phase 2 single-arm clinical trial in mCRC, the combination of Imprime with cetuximab resulted in 24% ORR, 62% disease control rate (DCR), and median time to progression (TTP) of 12 wks (Tamayo ME, Ann Onc 2010), representing approximate 100% increases vs historical control (Cunningham, NEJM 2004). ORR was 45%, DCR 82% and TTP 24 wks in pts with KRAS WT tumors (post hoc analysis). The current trial, sponsored by Biothera and registered with ClinicalTrials.gov NCT01309126, EudraCT 2010-023562-51, is to confirm these findings in phase 3. Trial design: Approximately 795 pts with previously treated, KRAS WT mCRC will be randomized 2:1 to weekly open-label Imprime plus cetuximab or cetuximab alone, until disease progression. Randomization will be stratified by geographic region, prior chemotherapy and site. The primary endpoint of the study is OS. Secondary endpoints are PFS, ORR (based on RECIST 1.1), quality of life, safety and pharmacokinetics. Exploratory endpoints include biomarker analyses. The primary analysis will occur when ∼709 deaths have occurred. Eligible pts have measurable disease, an ECOG performance status of 0 or 1 and have received prior oxaliplatin- and irinotecan-based therapy or are intolerant to irinotecan. Pts with known hypersensitivity to cetuximab or yeast are excluded. Pt screening and enrollment is underway in Europe and the United States. Disclosure: M.L. Patchen, M. Gargano, M. Grady, J. Lowe, R.D. Huhn and A. Braun: Author is a Biothera employee and has stock options and/or grants.

550P - Safety and Efficacy of Panitumumab (Pmab) Monotherapy in Recurrent or Progressive Metastatic Colorectal Cancer (Mcrc): Results from a Non-Interventional Study (Vectis)

ABSTRACT Aim: Pmab is an epidermal growth factor receptor (EGFR) inhibitor indicated for patients (pts) with wild-type RAS mCRC. EGFR inhibitors are associated with skin toxicity (ST) that is mild to moderate in severity for most pts (pts). VECTIS was designed to assess the safety and efficacy of pmab as monotherapy in daily practice with special reference to ST and its management. Methods: This was an open-label, prospective, non-interventional study of 632 pts who had EGFR-expressing wild-type KRAS mCRC and were receiving pmab monotherapy (6 mg/kg Q2W) according to the label at the time the study was initiated. The analysis includes data collected 2008-2013 from Hungary, Poland, Czech Republic, Slovakia, Slovenia, and Bulgaria. The observation period was limited to 18 cycles. The presence of non-zero correlation between best response and maximum ST was tested using chi-square test for non-zero correlation. Results: At time of reporting, 533/632 (84.3%) enrolled pts (64.6% males, median age 63.0 years) had experienced a total of 782 ST events, 43.2% Gr0-1, 56.8% Gr2-3. By the end of the study 29.2% of ST events had resolved; 2.0% had resolved with consequences; 24.2% were continued but improving; and 44.5% had not resolved. Overall, 69.8% of pts required therapeutic measures for ST. Of the 13 deaths that occurred, none was related to pmab. 5 pts have stopped pmab therapy due to adverse drug reactions including ST or other toxicity. Overall, 10.4% of pts have experienced tumor response (CR + PR), 58.9% have had disease control (CR + PR + SD), and 18.2% were reported to be free from progression (FFP) at the end of observation. A statistically significant positive correlation was observed between severity of ST and both best response (p = 0.0009) and tumor response (p = 0.0002). % (95% CI) Overall N = 632 ST Gr0-1 n = 273 ST Gr2-3 n = 359 CR + PR 10.4 (8.2, 13.1) 4.8 (2.6, 8.0) 14.8 (11.3, 18.9) CR + PR + SD 58.9 (54.9, 62.7) 53.8 (47.7, 59.9) 62.7 (57.4, 67.7) FFP 18.2 (15.3, 21.4) 13.6 (9.7, 18.2) 21.7 (17.6, 26.4) Conclusions: In clinical practice, pmab monotherapy was well tolerated and effective in pts who have recurrent or progressive mCRC with wild-type KRAS gene tumor status. Disclosure: R. Lakomy: has following interests to disclose: Advisory Board member - BMS, Research funding - BMS, GSK, Novartis, Roche, other relationship - remuneration from BMS (seminar presentation). no stock ownership; B. Piko: has following interests to disclose: Advisory board member - Roche, Bayer, Pfizer, other relationship - remunaration from Roche, Merck, Richter, Teva. No stock ownership, no research funding; Z. Mihaylova: has following interests to disclose: advisory board member - Lilly, Amgen, Merck, Sanofi. No stock ownership, no research funding, no other relationship; E. Pritzova: has following interests to disclose: research funding - Bayer, Pfizer, GSK. no stock, no advisory board member, no other relationship; L. Kvocekova: has folowing interests to disclose: stock - Amgen, other relationship - full time Amgen employee. no advisory board member, no research funding. All other authors have declared no conflicts of interest.

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

ObjectiveWe aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large...

Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.

To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC). miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings. After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P = 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r(2) = 0.49; P = 0.0035) and risk status determined by hsa-miR-31-3p expression level (P = 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFS-depending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy.

P-0239 - Toxicity Profile and Outcomes of Antiefgr Treatment in Elderly Patients with KRAS Wild-Type Metastatic Colorectal Cancer. Experience of Virgen DE Las Nieves University Hospital

Introduction: The treatment with antiEGFR therapy (Cetuximab or Panitumumab) is a standard treatment in KRAS wild-type (KRASwt) metastatic colorectal cancer (mCRC) in monotherapy or in combination with chemotherapy. Elderly patients (pts) are underrepresented in clinical trials. The aim of this study is evaluate toxicity profile and outcomes in elderly patients with KRASwt mCRC and treated with antiEFGR therapy alone or in combination with chemotherapy. Methods: It has carried out a retrospective study of 23 pts >70 years with KRASwt mCRC who were treated at our institution between February 2008-August 2013 with antiEGFR therapy. Results: The median age of pts was 75 years (70-85). 73% were men, and 27% were women. All pts had ECOG 0-1 and KRASwt mCRC. 91% of pts received Cetuximab weekly (30%) or biweekly (70%) and 9% received Panitumumab at standard dosage in first (30.4% of pts), second (34.8% of pts) o third line (34.8% of pts) of treatment. 30% of pts received monoclonal antibody (mAb) in monotherapy and 70% (16 pts) in combination with chemotherapy: 13% of pts received FOLFOX in combination, 18% received FOLFIRI and 63% of pts received Irinotecan. 31% of pts had a grade 3-4 toxicity related chemotherapy: 1 pt (6% of pts) experienced grade 4 neutropenia, 1 pt experienced grade 4 cardiovascular toxicity, 2 pts (12% of pts) experienced grade 3 diarrhea and 1 pt experienced grade 4 alopecia. No toxic deaths. 65% of pts had cutaneous toxicity related mAb: 73% grade 1-2 toxicity and 27% grade 3-4 toxicity. 35% of pts had diarrhea related mAb and only 2 pts experienced grade 3 diarrhea. 33% of pts (n = 3) experienced hypersensitivity reactions to Cetuximab. 39% of pts had other grade 1-2 toxicities related mAb: asthenia, pruritus and conjunctivitis. 43.5% of pts required dose reduction of the mAb due to toxicity. 3 pts stopped treatment with mAb due toxicity. Response Rate (RR) was assessable in 87% of pts: 35% had a partial response (PR), 10% had stable disease (SD) and 55% of pts had progression disease. Median Progression Free Survival (PFS) was 6.8 months (1.7-15.5) and median Overall Survival (OS) was 10.52 months (1.7-37.6). Conclusion: In our experience treatment with antiEGFR therapy in elderly pts with KRASwt mCRC is feasible, with a manageable toxicity, and effective with a clinical benefit (PR + SD) of 45%, a PFS of 6.8 months and an OS of 10.5 months in previously treated pts mostly (70% of pts).

BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer

The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non-BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients.

Randomized phase II study of panitumumab (Pmab) plus irinotecan (CPT-11) versus cetuximab (Cmab) plus CPT-11 in patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) following treatment with fluoropyrimidine, CPT-11, and oxaliplatin (L-OHP) chemotherapy: WJOG6510G.

TPS3654 Background: Pmab and Cmab are known to be effective in KRAS WT mCRC. Recent study showed that Pmab and Cmab monotherapy were comparable in patients with KRAS WT mCRC previously treated with...

Phase II study of FOLFOXIRI plus panitumumab (pmab) followed by evaluation for resection, in patients (pts) with metastatic KRAS wild-type colorectal cancer (mCRC) with liver metastases only.

e14552 Background: Pts with liver-only mCRC who are not candidates for potentially curative resection may be converted to resectable with more aggressive chemotherapy regimens with higher response rates (RR). FOLFOXIRI has shown a higher RR and pts sent to resection than FOLFIRI. EGFR inhibitors improve RR by approximately 10%. This phase II, non-randomized, multicenter trial evaluated the RR of the combination of FOLFOXIRI plus pmab as first-line treatment for pts with KRAS wild-type mCRC with liver-only metastasis. Methods: Pts with liver-only KRAS wild-type mCRC received FOLFOXIRI (5-FU 3200 mg/m2 48-hour continuous IV; LV 200 mg/m2 IV; irinotecan 125 mg/m2 IV; oxaliplatin 85 mg/m2 IV) and pmab (6 mg/kg IV) day 1 of each 14-day cycle. Restaging occurred every 4 cycles. Surgical evaluation occurred at baseline and with each restaging. The primary endpoint was overall RR. Secondary endpoints included: rate of R0 resection, progression-free survival (PFS), overall survival (OS), and safety. Results: Fifte...

Biweekly cetuximab plus FOLFIRI/irinotecan as first/second-line chemotherapy for patients with KRAS wild-type metastatic colorectal cancer: a retrospective analysis in Southwest Chinese population

Weekly cetuximab plus irinotecan-based regiments are standard first- and second-line chemotherapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC). However, the chemotherapy regimens are given every 2 weeks, which is asynchronous with cetuximab weekly administration. This study investigated the efficacy and safety of biweekly cetuximab administration in patients with mCRC. Twenty-six patients with KRAS wild-type mCRC, who received biweekly cetuximab plus FOLFIRI/irinotecan as first/second-line chemotherapy, at least three cycles of cetuximab and once CT evaluation in West China Hospital from May 2010 to February 2013, were retrospectively analyzed. The median number of cetuximab administrations was 8.3 (range 3-20). Fourteen patients received FOLFIRI as first-line therapy; response rate was 50.0%; median PFS was 8.8 months (95% CI 4.9-12.7). Ten patients received FOLFIRI and two patients received irinotecan as second-line therapy; response rate was 33.3%; median PFS was 4.6 months (95% CI 0.9-8.3). The toxicity was similar to weekly cetuximab combination schedules. Rash was observed in 69.2% of evaluable patients (grade 3 in 7.7%). Overall, our results show that biweekly cetuximab plus FOLFIRI/irinotecan may be as effective and safe as the standard weekly schedule.