KRAS Pts Research Articles

KRAS WT pancreatic adenocarcinomas: Another disease?

750 Background: KRAS mutation is the most common molecular alteration (MA) in pancreatic adenocarcinoma (PDAC), and only 8-10% of patients (pts) harbor KRAS wild-type tumors (WT). This study describes clinical and molecular features of KRAS WT PDAC and compares it to mutant KRAS (m KRAS) PDAC. Methods: A retrospective chart review of clinical/molecular data was performed on all pts with PDAC who had contributive molecular profile at Gustave Roussy. KRAS status was determined on tumor molecular profiling as part of routine care using an in-house panel or Foundation Medicine NGS either on tissue (63%) or liquid biopsy (37%). Results: Overall, 41 pts with KRAS WT PDAC were compared to 197 pts with mKRAS PDAC. Median OS (mOS) from initial diagnosis was significantly higher in the KRAS WT group compared to mKRAS group (32.8 months (mts), CI95% [25.9-NR] vs 21.5 mts, CI95% [18.8-24.9] respectively), as mOS from metastatic diagnosis, 26 mts, CI95% [15.7-NR] for KRAS WT pts vs 17.7 mts CI95% [15.5-19.3] for mKRAS (all p<0.05)). After adjustment on gender, age, metastasis status at diagnosis, hazard ratio (HR) of OS from metastatic stage diagnosis associated with KRAS status was 1.9 [1.1;3.4], p=0.02 (similar for 1st line PFS and OS from initial diagnosis). MA were found in 31 KRAS WT pts (76%). KRAS WT and m KRAS pts harbored different molecular profiles with less alterations of TP53, SMAD4 and CDKN2A/B (p<0.05) in KRAS WT tumors, but more of BRAF (p<0.05), PALB2, RET and BRIP1 (p=NS) alterations. Interestingly, 3 MSI tumors were found in the KRAS WT group (one received immunotherapy), vs none in m KRAS group). Tumor mutational burden was similar (2.00 Mut/Mb in KRAS WT pts vs 2.7 Mut/Mb in m KRAS pts). Based on ESCAT classification, a putative therapeutic target (ESCAT I-IV, other than KRAS) was identified in 15 (36%) KRAS WT pts and 65 (33%) m KRAS pts, thus enriching the therapeutic panel for these patients. Indeed, for example 9 (22%) KRAS WT pts received an oriented therapy after palliative treatments (such as anti-RET or anti-PARPs) and showed higher survival rates compared to KRAS WT pts who did not (mOS from diagnosis in months NR (14.2; NR) and 28.3 (26; NR) respectively). Conclusions: In our cohort of 238 PDAC, we confirm that KRAS is a prognostic factor of OS. KRAS WT PDAC have a significantly longer OS compared to m KRAS. Moreover, 36% of KRAS WT PDAC pts had a potentially actionable MA, and 9 pts displayed higher survival rates after receiving oriented therapies. This study suggests that KRAS WT PDAC should be eligible for a large molecular screening.[Table: see text]

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, in patients (pts) with metastatic colorectal cancer (mCRC): Exploratory analysis according to KRAS status in the gercor DREAM phase III trial.

448 Background: In the GERCOR-DREAM trial, maintenance therapy (MT) with bev + EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC significantly improved PFS compared with bev alone. Here we explore the influence of KRAS status on erlotinib efficacy. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). KRAS determination was established by local assessment in each center. Results: Among the 452 randomized patients, KRAS status was available in 403 pts (89%): 234 pts (58%) KRAS wt and 169 pts (42%) KRAS mut. Clinical characteristics were similar between both populations. For the whole population of randomized patients (n=452), median PFS from inclusion were 9.33m and 10.55m in arm A and B, respectively (HR=0.76 [0.61-0.94], p=0.011). For KRAS wt population, median PFS from inclusion was 9.66 m and 10.94 m in arm A and B, respectively (HR=0.80 [0.59-1.08], p=0.141). For KRAS mut population, median PFS from inclusion was 9.79 m and 9.79 m in arm A and B, respectively (HR=0.86 [0.61-1.22], p=0.393). In KRAS wt pts treated with erlotinib, cutaneous toxicity was predictive of PFS: mPFS was 9.66m in pts with grade 0 (n=101) and 10.91m in pts with grade ≥1 (n=114) (HR=0.69 [0.51-0.95], p=0.0186). Conclusions: The addition of erlotinib to bevacizumab as maintenance treatment in first-line metastatic colorectal cancer significantly improves progression-free survival from inclusion. However, in both wt and mut KRAS pts, difference was not statistically significant. Unlike anti-EGFR monoclonal antibodies, the addition of erlotinib to bevacizumab does not appear to be antagonist in KRAS mutant patients. Clinical trial information: NCT00265824.

580P - Hepatic Arterial Infusion (HAI) of Oxaliplatin Plus Intravenous (IV) Fluorouracil (FU), Leucovorin (LV) and Cetuximab for First-Line Treatment of Unresectable Colorectal Liver Metastases (CRLM): Final Results of a Multicenter Phase 2 Study (CHOICE)

ABSTRACT Background To determine the efficacy and tolerance of HAI oxaliplatin plus iv FU/LV and cetuximab in patients (pts) with unresectable CRLM. Methods Main eligibility criteria for this phase 2 study were: histologically proven colorectal adenocarcinoma; tumor wild-type (wt) KRAS status (protocol amendment in 09/2008); unresectable CRLM; no extrahepatic disease (except primary with absent/mild symptoms, and ≤ 3 nonspecific lung nodules ≤ 5 mm in diameter); no prior chemotherapy for metastatic disease; WHO performance status 0-1. After surgical or percutaneous insertion of an implantable HAI catheter, pts were treated with HAI oxaliplatin (100 mg/m2 in 2 hrs) plus iv modified LV5FU2 regimen (LV, 400 mg/m2 in 2 hrs; FU, 400 mg/m2 bolus then 2400 mg/m2 in 46 hrs) every two weeks plus iv cetuximab (400 mg/m2 then 250 mg/m2/week, or 500 mg/m2 every two weeks) until disease progression, limiting toxicity, or CRLM resection. Primary endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints included toxicity (NCI CTC-AE v3.0), disease control rate (DCR), resection rate, progression-free survival (PFS), and overall survival (OS). Results A total of 36 pts were included in 8 centers from 11/2006 to 12/2009. Most of the 35 eligible pts (male, 63%; median age, 54 yrs [range, 33-75]) had extensive disease (≥ 4 CRLM, 88%; bilobar CRLM, 91%). Pts received a median of 10 cycles (range, 1-41). Main severe toxicity was abdominal pain (40%), neutropenia (37%), peripheral neuropathy (34%) and rash (29%). Among 32 evaluable pts, ORR was 87% and DCR was 97%. Among the evaluable pts with wt KRAS (n = 27) or wt KRAS/BRAF (n = 24) tumor status, ORR were 89% and 96% and DCR 96% and 100%, respectively. Overall, 23 of the 35 pts (66%) underwent curative-intent resection and/or radiofrequency ablation (wt KRAS pts, 21 [70%]; wt KRAS/BRAF pts, 20 [74%]). After a median follow-up of 48 months, median PFS was 29 months (median OS, not reached). Conclusions First-line HAI oxaliplatin plus iv LV5FU2 and cetuximab seems feasible and highly effective in pts with unresectable CRLM. Disclosure D. Malka: Membership on an advisory board: Roche Research funding: Amgen, Merck Serono, Sanofi-Aventis. M. Ducreux: Membership on an advisory board: Roche, Pfizer, Sanofi-Aventis, Merck Serono, Amgen Research funding: Roche, Merck Serono, Pfizer. All other authors have declared no conflicts of interest.

PD-0015 Influence of BRAF V600E and Different Kras Mutations on Outcome of Metastatic Colorectal Cancer Patients Treated with First- Line Therapy

ABSTRACT Introduction KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti- EGFR monoclonal antibodies. Recent retrospective studies suggested that patients (pts) with different KRAS mutations (KRAS mts) respond different to specific systemic therapy and also pts with KRAS mt in codon 13 might respond to anti- EGFR monoclonal antibodies but with lower response rates than pts with KRAS wild-type (KRAS wt) tumors. Methods Objective response (OR), time to progression (TTP), overall survival (OS) and BRAF status in metastatic colorectal cancer (mCRC) pts treated with first- line therapy according to KRAS status, were retrospectively analyzed. Results In total 176 mCRC pts who received first- line therapy between May 2009 and October 2010 were included in retrospective analysis. The median age was 62 years (27- 86), M/F 61/39 %. The most common received therapies were XELIRI/bevacizumab and XELOX/cetuximab in 29.5 % and in 22.1 % of pts respectively. KRAS mts were found in 63 pts (35.8 %), mt KRAS in codon 12 in 53 pts (84%) and mt KRAS in codon 13 in 10 pts (16%). BRAF V600E mt was detected in 13 of 176 pts (7.4%). OR in wt KRAS/wt BRAF pts was 54% (CR 14.7 %, PR 39.3 %) and in wt KRAS/mt BRAF pts was 38.5% (CR 15.4 %, PR 23.1 %), difference (diff) was not statistically significant (p= 0.378). Median OS of wt KRAS/wt BRAF pts and wt KRAS/mt BRAF pts was 107.4 months (mo) (95% CI: 82- 132.9 mo) and 45 mo (95% CI: 28.4- 61.5 mo) respectively, diff was statistically significant (p= 0.042). TTP in wt KRAS/ wt BRAF pts and wt KRAS/mt BRAF pts was 16 mo (95% CI: 10.7- 21.2 mo) and 12 mo (95% CI: 4.0 -15.0 mo) respectively, diff was not statistically significant (p= 0.558). OR in codon 12 mt pts was 47% (CR 20.7%, PR 26.3%) and in codon 13 mt pts was 33% (CR 11%, PR 22%),dif was not statistically significant (p= 0.08). TTP in mt codon 12 pts and mt codon 13 pts was 13.5 mo (95% CI: 9.0- 18.0 months) and 9.3 mo (95% CI: 5.1- 13.5 mo) respectively, diff was not statistically significant (p= 0.106). Conclusion Mt BRAF pts have statistically significantly worse prognosis than wt BRAF pts, with lower response rates and progress earlier during systemic treatment. Codon 13 mt KRAS pts have lower response rate and progress earlier than KRAS codon 12 mt pts. Definitive role of mt BRAF and different KRAS mts are needed to be defined to select pts, who will benefit from specific combination of systemic therapy.

Clinical characteristics of KRAS mutations in NSCLC and their impact on outcomes to first-line chemotherapy.

7588 Background: KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). While the impact of EGFR mutations and EML4-alk translocations has been well-described, there is limited information about the impact of these somatic mutations on response to chemotherapy. Methods: We retrospectively reviewed the demographics and clinical outcomes of patients with KRAS mutations and compared these to patients who were KRAS wild-type (WT). Eligible pts received 1st-line IV chemo for stage IV NSCLC at DFCI and had known information about both KRAS and EGFR status. Since the biology and impact of EGFR mutations on response to chemo is well-described, we excluded such pts from the analysis. The primary endpoint was progression-free survival (PFS) with first-line chemo; secondary endpoints included radiographic response rate (RR) and overall survival (OS). Results: Between 2/05 and 8/11, there were 63 eligible KRAS pts and 97 eligible WT pts. The groups were similar in age (median 65yrs in both groups), % female (K 62, WT 54) race (K 89% white/6% black, 5% other; WT 86% white,/6% black/8% other), histology (K 90%adeno/8% NSCLC NOS; WT 86% adeno/9%NSCLC NOS), and % of pts receiving 1/2/3 agents in 1st line (K 11/56/33; WT 18/53/30). KRAS pts were less likely to be never or light smokers (4% vs 33% for WT). Nonsmokers were more likely to harbor KRAS transition rather than transversion mutations (3 transition, 1 transversion), while the converse held for smokers (51 transversions, 8 transitions). Median PFS was similar for KRAS vs WT (K .65 vs WT 4.8 months, p=0.81). RR (29% for both groups), disease control rates (K 73% vs WT 78%), and median OS (K 13.5 vs WT 12.1 months, p=.525) were also similar. Outcomes of KRAS pts to 2nd line chemotherapy (PFS 2.2, OS 8.6) are similar to those seen for WT patients in this setting. There was no significant difference in outcomes based on gender, smoking status, drug received (pemetrexed-based vs taxane based), or specific KRAS genotype. Conclusions: Pts with KRAS mutations experience similar outcomes to standard chemotherapy as those who are wild-type for EGFR and KRAS. Going forward, these data can serve as a reference for control arms of KRAS-specific randomized trials.

Incidence and patterns of phospho insulin growth factor receptor-1 (pIGF-1R) and matrilysin (MMP7) expression in metastatic colorectal cancer (mCRC), and correlation with KRAS status: A prospective evaluation in the PULSE trial—A GEMCAD study.

e14041 Background: MMP7 can activate IGF-1R by IGF release due to IGFBP degradation. Activation of IGF-1R can contribute to EGFR resistance by transactivation. We previously described that concomitant expression of p-IGF-1R and MMP7 (Double positive; DP), correlates with poor prognosis, in KRAS WT patients (pts) treated with anti-EGFR compounds (Horndler el al, 2011). Therefore we designed a prospective clinical trial to validate DP as a marker of resistance in KRAS WT pts treated in first-line therapy with FOLFOX-6 plus panitumumab. Methods: mCRC pts in the ongoing prospective PULSE trial (NCT0128833) were prospectively evaluated for p-IGF-1R (p-1316), MMP7 expression and KRAS mutational status. Pts defined as DP should express MMP7 (++ or +++ intensity in >66% of tumor cells) and p-IGF-1R (++ or +++ intensity in >66% of tumor cells). KRAS pts with mutations at exon 2 were excluded. The study was designed to include 40 pts in the two groups (DP vs non-DP) to detect a Hazard ratio difference in PFS of <0.5 (DP vs non-DP) with 80% power. Results: From November 2010 to December 2011, 113 consecutive pts were screened from 24 Spanish Institutions. 54 KRAS WT (40 pts non-DP and 14 DP) have been included. The non-DP arm has being recently closed for inclusion, due to pre-planned complete accrual. Among DP pts, 27% were KRAS WT and 30% KRAS mutant; p=0.63. 48% of cases were positive for p-IGF-1R. Phospho-IGF-1R positive cases had different patterns of staining: peri-nuclear in 76%, 11% nuclear and only 13% membrane-apical staining. These patterns do not differ between KRAS WT; (n=70) and KRAS mutant pts (n=43) (p=0.60). Tumors with positive p-IGF-1R expression, independently of the pattern, have higher MMP7 co-expression (59%) compared with negative cases (13%) (p<0.0001). Conclusions: MMP7 contributes to activate IGF-1R pathway in pts with mCRC. Internalization of the activated IGF-1R, could explain in part, the lack of efficacy of IGF-1R inhibitors in mCRC clinical trials.

PULSE: An open-label, phase II study assessing double positivity (phospho-insulin-growth factor receptor-1 [pIGF-IR] and matrilysin [MMP7]) expression as a predictive marker of resistance in previously untreated metastatic colorectal cancer (mCRC) wild-type KRAS patients (pts) treated with panitumumab plus mFOLFOX6—A GEMCAD study.

TPS164 Background: By transactivaction, p-IGF-IR can activate epidermal growth factor receptor (EGFR). Matrilysin (MMP-7), can activate IGF-IR by degrading IGFBP-3 and releasing IGF-I. Concomitant expression of MMP-7 and p-IGF-IR (using a specific monoclonal antibody (p-1316) recognizing the phosphorylated carboxy-terminal part of the IGF-IR) (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR antibodies plus irinotecan (Horndler et al, Cancer Biol Ther 2011). Methods: Trial Design: the primary objective of this trial is to estimate the progression free survival (PFS) by DP immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC treated with panitumumab and mFOLFOX6. Two groups are established by DP status (MMP7+/p-IGF-IR+ vs. MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR-). With a power of 80% and a bilateral alpha level of 0.05, assuming an accrual period of 12 months (m) and a follow-up period of 18 m, 40 patients are planned to be included in each group to detect a Hazard Ratio of 2. The median PFS of the DP group is expected to be 6 m and the total number of expected events is 56. Secondary objectives include disease control rate, duration of response, time to response and survival according the DP status. Treatment: Both groups will receive panitumumab 6 mg/kg and mFOLFOX6 every 2 weeks. If pts have not progressed after 6 m of treatment they will continue with panitumumab monotherapy until disease progression. Major eligibility criteria: Previously untreated wild type KRAS mCRC, ECOG PS of 0 or 1, at least 1 unidimensionally measurable lesion, and age > 18 years. Correlative studies: PTEN and p-EGFR by IHC and BRAF, PI3K, PTEN, IGFR-II, EGFR (3’) and NRAS mutations according microsatellite instability. Blood sample collection (MMP-7, IGFBP-2,3,5, IGF-I and IGF-II) basally and every 2 month until progressive disease. The study has just initiated enrollment.

Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: A GEMCAD study

Background: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I.Methods: A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses.Results: Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis.Conclusions: Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.See commentary: MMP7 and activation of IGF-1R: A new insight into anti-EGFR therapeutic resistance in metastatic colorectal cancer

Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): PRIME trial analysis by epidermal growth factor receptor (EGFR) tumor staining.

3566^ Background: This study evaluated the efficacy and safety of pmab + FOLFOX4 versus FOLFOX4 alone as first-line tx for mCRC by tumor KRAS status; analyses by EGFR staining were also performed. Methods: Pts who received no prior chemotherapy for mCRC and no prior oxaliplatin were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFOX4 (Arm 1) or FOLFOX4 alone (Arm 2). The primary endpoint was progression-free survival (PFS); overall survival (OS) was secondary. PFS and OS were prospectively analyzed according to KRAS status. Using the Dako EGFR pharmDx immunohistochemistry kit, tumor tissue sectioned within 2 months prior to testing was evaluated for EGFR staining. EGFR results were not required for study entry. Results: 1,183 pts were randomized. Demographics and baseline characteristics were generally balanced. 1,096 pts (93%) had KRAS results. For WT KRAS, median PFS was 9.6 mos for Arm 1 and 8.0 mos for Arm 2; median OS was 23.9 mos for Arm 1 and 19.7 mos for Arm 2. 813 (69%) pts had EGFR results. The most common reason for no EGFR result was tissue section ≥2 months old. Of 479 WT KRAS pts with EGFR results, 326 (68%) were EGFR+. The Table shows the treatment effect within the subpopulations by EGFR staining. No treatment effect by EGFR staining was observed in a stratified multivariate Cox model evaluating the predictive effect of EGFR parameters on PFS (p = 0.89) and OS (p = 0.43) in KRAS WT pts. Except for known toxicities associated with anti-EGFR tx adverse event rates were generally comparable across arms. Conclusions: When added to FOLFOX for first-line mCRC tx, pmab significantly improves PFS and is well tolerated in pts with WT KRAS. A consistent effect of pmab on PFS and OS was observed in both EGFR+ and EGFR- subsets. Further results by EGFR staining parameters will be presented. Efficacy by EGFR membrane staining-WT KRAS WT KRAS N = 656 EGFR evaluable WT KRAS N = 479 HR (95% CI) p value HR (95% CI) EGFR+ HR (95% CI) EGFR- PFS* 0.80 0.77 0.80 Pmab FOLFOX : FOLFOX (0.66-0.97) 0.02 (0.58-1.03) (0.53-1.21) OS 0.83 0.77 0.64 Pmab FOLFOX : FOLFOX (0.67- 1.02) 0.07 (0.52-1.13) (0.34-1.18) * By blinded central review. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen, AstraZeneca, Celgene, Fresenius Biotech, Merck Serono, Roche, sanofi-aventis Amgen Amgen, Merck AG, Merck Serono, sanofiaventis Amgen, Merck AG, Merck Serono, Pfizer Amgen In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Serum IGFBP3, IGF-I, and MMP7 changes in advanced colorectal cancer (ACRC) patients (pts) treated with anti-EGFR therapy: A GEMCAD study

e15109 Background: Insulin-like growth factor-I (IGF-I) is a potent mitotic and anti-apoptotic peptide, whereas IGF binding protein-3 (IGFBP3) seems to have pro-apoptotic effects. Matrix metalloproteinase-7 (MMP7), an enzyme with in vitro ability to degrade IGFBP3, has been shown to be a prognostic factor in ACRC. Methods: This is a prospective single cohort traslational study. Pts undergoing second/third line with irinotecan plus anti-EGFR therapy were eligible as cases. Patients with ACRC not undergoing therapy were eligible as controls. IGFBP3 and MMP7 were measured in serum with immunoassays at baseline and at 48h after treatment start. KRAS mutation status in codons 12/13 was determined by sequencing in 53 pts. The primary endpoint is to define the IGFBP3 and MMP7 variation under anti-EGFR therapy. IGFBP3 was used as a continuous variable and MMP7 was used to create two groups by its third quartile. Results: Eighty-five cases and 25 controls were recruited. No significant changes at 48h in IGF-I and IGFBP3 were found, but a significant decrease in MMP7 from 10.8 (95%IC 8.3–13.3) to 8.4 ng/ml (95%IC 6–10.9) was observed in cases (p<0.001) in contrast with controls, where no changes were found. Splitting the sample by the third quartile of MMP7 interesting changes in IGFBP3 variations were found. In the group with low levels of MMP7, IGFBP3 increases from 1,859 to 1,959 ng/ml (p=0.043) 48h after treatment initiation; on the contrary, in the group with high levels of MMP7, IGFBP3 decreases from 1,811 to 1,757 ng/ml (p=0.741). We found no association with IGFBP3 and neither response rate, time to progression nor overall survival. This latter analysis was also done only in pts with wild-type KRAS, without any change in the results. Conclusions: In pts with ACRC treated with anti-EGFR therapy, serum levels of IGFBP3 variations depend on basal MMP7 levels. IGFBP3 failed to be a predictive/prognostic factor in our sample although the limited number of KRAS pts analyzed can influence our results. [Table: see text] No significant financial relationships to disclose.

Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series

4035 Background: Cetuximab, a monoclonal antibody (mAb) directed against the epidermal growth factor receptor (EGFR), is approved in combination with irinotecan (Iri) for the treatment of Iri-refractory metastatic colorectal cancer (MCRC) expressing EGFR. Recent studies have shown that KRAS mutation (mut) confers resistance to anti-EGFR mAbs. We extracted data of 281 patients (pts) from 7 series (Lievre 2006 and 2008, Moroni 2005, Di Fiore 2007, De Roock 2007, Benvenuti 2007, Frattini 2007) to determine the role of KRAS mut in Iri-refractory MCRC patients treated with cetuximab plus Iri based-chemotherapy (CT). Methods: The following data were collected: sex, age, previous CT lines, anti-EGFR regimen, response rate based on RECIST criteria, progression-free survival (PFS), overall survival (OS) and KRAS mutational status. Response rate was evaluated using the Fischer exact test. PFS and OS were calculated using the Kaplan-Meier method and compared with log-rank test. Predictive factors of response and survival were determined by logistic regression and Cox-regression model, respectively. Results: A total of 281 pts were included, 174 men and 107 women with a mean age of 59.8 yrs. Pts received a mean of 2.4 prior CT lines. 77 pts (27.4%) responded (3 complete response (CR) and 74 partial response (PR)), 107 (38.1%) had stable disease (SD) and 97 (34.5%) had disease progression (PD). A KRAS mut was detected in 98 pts including 40/107 (37.4%) pts with SD and 58/97 (59.8%) with PD. All responders were KRAS wild-type. KRAS mut was significantly associated with PD (p< 0.0001). Median PFS and OS were significantly lower in mutated KRAS pts, 12 weeks (wks) vs 24 wks (p<0.0001) and 36 wks vs 44 wks (p<0.0001), respectively. The absence of KRAS mut was identified as predictive factor of disease control (CR+PR+SD) (p<0.0001,OR:0.17;95IC:0.10–0.30) and OS (p<0.0001,OR:0.51;95IC:0.37–0.70), respectively. Conclusions: KRAS mutational status plays a key role in response rate, PFS and OS in Iri-refractory MCRC pts treated with cetuximab and Iri. Our results demonstrate the potentially major impact of KRAS mutation in pts selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Merck Merck Amgen