KRAS Wild-type Pts Research Articles

Mutated KRASas a promising target in pancreas cancer: PURPLE registry data to inform real-world incidence and prognostic significance and to aid trial recruitment.

11150 Background: With around 90% KRASmutation (mt) frequency, pancreatic ductal adenocarcinoma (PDAC) is considered the most RAS-addicted cancer. Despite guideline recommendations, genomic testing is not routine in all PDAC patients (pts) in Australia, due to unproven clinical impact. As more novel KRAS-direct therapeutics enter clinical trials, understanding the real-world frequency of individual mutations and prognostic significance, and facilitating trial recruitment are important goals, all of which can be supported by registry data. Methods: Data extracted from the PURPLE pancreatic cancer registry from 9 participating Australian cancer centres, between 2016-2022, was analysed to compare clinicopathological features, survival based on KRASmt status, and assess feasibility of the platform to identify and molecularly stratify patients for future clinical trials. Survival estimates were calculated using Kaplan-Meier curves and log-rank testing on SPSS (Macintosh v.29). Results: Of 721 PDAC routine care pts identified, next generation sequencing (NGS) was undertaken in 378/721 (52%). Median patient age was 68 years (range 52-83); 152 (40%) had resectable, 111 (29%) locally advanced and 115 (30%) metastatic disease. 57/378 (15%) were KRAS wildtype. Of 321 pts with a KRAS mt, codons 12,13, and 61 were the most common sites of mt, including G12D (45%), and G12V (30%), with lower frequencies of G12R (13%), Q61H (6%), G12A (3%), G12C (1%), and G13D (1%). Comparing KRAS wildtype to KRASmt pts, there was no difference in median age (68 vs 67, p=0.63), gender (male: 49% vs 60%, p=0.23), Charlson comorbidity index (p=0.30), or stage at first presentation (p=0.99). Overall KRAS wildtype pts were more likely to be ECOG PS 0 at diagnosis (p=0.01) and to receive at least 1 modality of treatment (p=0.004). For all pts, median overall survival (OS) in KRASwildtype versus KRAS mt pts was 29.0 months versus 19.7 months (p=0.007), and for the 115 metastatic pts 15.1 versus 10.4 months (p=0.28). Further analysis of the impact by disease stage and by individual RAS mt is underway. Conclusions: Registry based analysis informs understanding of KRAS mt status of PDAC in a community setting. Here, KRAS mt status was associated with worse OS outcomes, likely in part due to the association with ECOG PS and receiving less active treatment. With newer promising KRAS-targeted therapies becoming available in clinical trials, known RAS status will aid identification of trial candidates. The clinical utility of NGS and rationale for reflex testing in PDAC is increasing. Clinical Registry information (ACTRN12617001474347).

Impact of PD-L1 and KRAS status on the efficacy of nintedanib (NIN) + docetaxel (DOC) following treatment with first-line immune checkpoint inhibitor (ICI) + chemotherapy in patients with adenocarcinoma NSCLC: Analysis of cohort C of the non-interventional VARGADO trial.

e21149 Background: The identification of targetable molecular tumor markers in patients (pts) with NSCLC has increased significantly over the past decades and has resulted in important changes to individual treatment approaches. One such marker is KRASG12C for which a specific treatment is now available following prior systemic therapy. While ICIs ± chemotherapy represent first-line (1L) standard of care, the sequence of subsequent effective therapies still needs to be investigated. Methods: Cohort C of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) is investigating the combination of NIN + DOC as second-line (2L) treatment after prior 1L ICI + chemotherapy in pts with adenocarcinoma NSCLC. This updated analysis of Cohort C focuses on the safety and efficacy of NIN + DOC according to programmed death ligand-1 (PD-L1) and KRAS status. Results: At the cut-off date (December 1, 2022) 219 pts have been enrolled to Cohort C. Median age was 64 years (range: 37–84) and 58.9% (129/219) of pts were men. At baseline, 30.6% (67/219) were ECOG PS 0 and 50.2% (110/219) were ECOG PS 1. 88.1% (193/219) had stage IV disease. Brain metastases were present in 19.2% (42/219) of pts and 88.1% (193/219) had received prior 1L pembrolizumab-based combination therapy. In the overall population, median PFS was 4.5 months (mo; 95% CI: 3.6–5.3, 219 pts) and median OS was 9.6 mo (95% CI: 6.5–11.2, 217 pts) with NIN + DOC. KRAS mutation status has been documented for 119 pts. In KRAS wild-type pts (75/119), median PFS was 3.7 mo (95% CI: 2.6–5.3) and median OS was 7.7 mo (95% CI: 5.2-11.2). In KRAS mutation-positive pts (44/119) median PFS was 5.1 mo (95% CI: 3.4–6.3) and median OS was 6.7 mo (95% CI: 5.3–15.1). In 33 pts with a non-G12C KRAS mutation, median PFS was 5.0 mo (95% CI: 3.4–6.7) and median OS was 6.7 mo (95% CI: 5.3–15.1). ORR was 20.0% (15/75), 25.0% (11/44), 27.3% (9/33) and 18.2% (2/11) in pts with KRAS wild-type, KRAS mutated, non-G12C mutated and G12C mutated status, respectively. The corresponding disease control rates (DCR) were 45.3% (34/75), 47.7% (21/44), 48.5% (16/33) and 45.5% (5/11). PD-L1 status prior to 1L therapy was < 1% in 86 pts and ≥1% in 76 pts and did not impact OS (median 10.6 mo [95% CI: 6.5–15.1] and 10.5 mo [95% CI: 5.7–12.5], respectively) or DCR (51.2% and 51.3%, respectively) with NIN + DOC. The most frequent NIN-related adverse events of any grade in the overall population were diarrhea 34.7% (76/219), nausea 14.2% (31/219), vomiting 8.2% (18/219) and fatigue 7.8% (17/219). Conclusions: NIN + DOC is an effective and safe 2L treatment option after prior 1L ICI + chemotherapy for NSCLC adenocarcinoma pts independent of PD-L1 and KRAS status. Clinical trial information: NCT02392455 .

Targeted therapy (TT) in patients with KRAS wildtype (WT) pancreatic ductal adenocarcinoma (PDAC) produces durable response.

596 Background: Genomic alterations (GA) that drive cancer development and predict therapeutic response remain elusive in patients (pts) with KRAS WT PDAC. We interrogated our institutional database to identify actionable GAs in pts with metastatic, KRAS WT PDAC and analyzed the therapeutic impact of matched TT. Methods: We reviewed electronic medical records of KRAS WT PDAC pts (n=24) who underwent comprehensive genomic profiling (CGP) utilizing Foundation One CDx (25.0%) or Tempus (75.0%) between 2015-2021. Duration of response (DOR) was calculated from date of treatment (Tx) initiation to Tx discontinuation. Overall survival (OS) was measured from the date of the diagnosis (Dx) of advanced disease (AD) to death or last follow-up. OS was estimated using the Kaplan-Meier method, with at-risk periods left-truncated at the time of CGP. The effect of covariates on survival was evaluated using Cox proportional hazards regression. Results: Of the 24 KRAS WT pts, 14 (58%) had AD: 8 (57%) pts had metastatic disease at or shortly after Dx, 6 (43%) pts developed metachronous recurrence. Median age at Dx for pts with AD was 65, and 57% were female. Seven of 14 pts with AD (50%) had highly actionable GA (HAGA), (Table). Pts with HAGA demonstrated durable responses to TT (Table) with manageable toxicities. Pts with HAGA had a median OS of 28 mo compared to 5.9 mo for those without (Hazard Ratio = 0.47, p = 0.33). Conclusions: The sustained therapeutic benefit noted with TT matched to HAGA in pts with KRAS WT PDAC underscores the need for systematic interrogation of the somatic genome in PDAC pts. Optimal sequencing of cytotoxic therapy with TT and its impact on modulating clonal selection pressure in pts with KRAS WT PDAC merits prospective evaluation.[Table: see text]

Abstract 660: Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations

Abstract Introduction: KRAS mt are common in lung cancer, with G12C mt being the most prevalent in pts with aNSCLC. This study assessed pts with KRAS G12C aNSCLC with or without STK11 or KEAP1 mt. Methods: Pts diagnosed with aNSCLC between Jan 2011 and Dec 2019 in the US-based de-identified Flatiron Health-Foundation Medicine clinico-genomic database were included. Cox proportional hazards models adjusted for baseline demographics and clinical characteristics were used to analyze the effect of mutational status on OS in pts receiving immunotherapy (CIT), chemotherapy (chemo) or both (CIT+chemo). Results: Of 2217 1L pts, 454 (20.5%), 344 (15.5%) and 163 (7.4%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. Of 1019 2L pts, 234 (23.0%), 191 (18.7%) and 88 (8.6%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. A higher proportion of pts with KRAS G12C were females, PD-L1+ and had nonsquamous histology vs KRAS wildtype (WT) pts. Pts with KRAS G12C tumors had a higher cumulative incidence of mets (31.5% vs 25.8%) and brain mets (26.1% vs 18.8%) vs WT pts (P<0.001). No statistically significant difference was seen in the association of KRAS status with OS when stratifying by treatment type. In KRAS WT pts, STK11 mt vs WT pts had shorter OS in 1L (6.1 vs 9.4 mo) and 2L (4.5 vs 7.6 mo; Table); a similar trend was seen for pts receiving 1L CIT+chemo. In KRAS G12C pts, KEAP1 mt vs WT pts had shorter OS in 1L (4.9 vs 13.4 mo) and 2L (1.8 vs 9.4 mo); similar differences were seen in pts receiving 1L CIT+chemo or chemo. Conclusions: In pts with aNSCLC and KRAS WT, STK11 mt was associated with significantly worse OS; KRAS G12C co-occurring with KEAP1 mt had a similar result. Pts with STK11/KEAP1 mt have poor prognosis and high unmet medical need. This analysis highlights the importance of evaluating genomic alterations in clinical practice to better understand the interplay between treatment and survival. Table. Effect of KRAS mutational status and co-occurring known and likely STK11 and/or KEAP1 mutations on OS in patients with aNSCLC receiving any type of 1L or 2L therapy1L*2L†nMedian, mo (95% CI)HR‡ (95% CI)nMedian, mo (95% CI)HR‡ (95% CI)KRAS G12CSTK11WT32412.0(9.6-16.0)1.30(0.97-1.75)1699.2(7.8-11.4)1.05(0.68-1.63)STK11mt1047.5 (5.1-10.9)545.5(2.5-15.7)KEAP1WT35413.4(10.6-16.2)2.98§(1.91-4.64)1829.4(8.1-13.1)4.02§(2.10-7.70)KEAP1mt304.9(3.1-7.8)141.8(1.5-10.2)KRAS WTSTK11WT14599.4(8.5-10.6)1.57§(1.31-1.87)8477.6(6.5-8.8)1.66§(1.31-2.11)STK11mt2406.1(5.2-7.8)1374.5(3.5-7.6)KEAP1WT14059.3(8.3-10.5)1.43§(1.15-1.78)8137.6(6.4-8.8)1.25(0.93-1.68)KEAP1mt1336.2(4.7-7.8)744.9(3.3-8.0)1L, first line; 2L, second line; aNSCLC, advanced non-small cell lung cancer; HR, hazard ratio; Mb, megabase; mt; mutation; OS, overall survival; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; WT, wildtype.*Adjusted by age, sex, race, cancer type (de novo or recurrent), histology PD-L1 status, any metastases, TMB (mutations per Mb: <10 and ≥10), histology and treatment type.†Adjusted by age, sex, race, cancer type (de novo or recurrent), histology, PD-L1 status, any metastases, TMB (mutations per Mb: <16 and ≥16), histology and treatment type in 1L and 2L.‡HR comparing WT vs STK11 mt+ or KEAP mt+.§P<0.001. Citation Format: Cristina Julian, Navdeep Pal, Anda Gershon, Maria Evangelista, Hans Purkey, Peter Lambert, Zhen Shi, Qing Zhang. Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 660.

Analysis of the relationship between different prognosis factors in patients with advanced colon cancer and progression-free survival.

e15518 Background: Colon tumors are a heterogeneous group of disease. As a result of the accumulation of different genetic and epigenetic alterations, the mutation of the RAS, BRAF oncogene and microsatellite instability stands out. A new line of research are immunological and inflammatory factors, the infiltrating lymphocytes of the tumor stroma (TILs) and the neutrophil to lymphocyte radio (NLR) have been studied by our work team. We understood could that these factors were associated with the survival rate in our patients. The main objective of this reseach is to determine the relationship between NLR and progression-free survival (PFS) in patients with advanced colon cancer. Secondary objective is to determine the relationship between the location of the primary tumor, RAS status, TILs, and PFS. in the same group of patients. Methods: A total of 93 medical records of patients with advanced colon cancer was analyzed. Those pts who had recieved first-line chemotherapy treatment with a FOLFOX scheme plus a monoclonal antibody were included. All patients had to have a minimum follow-up of 12 months. Regarding NLR, the patients were classified into two groups: high ( = > 4) and low ( < 4). Four TILs cut-off points were determined: > 40% intense; between 11-40% moderate, 1-10% mild, and 0% absent, which were group into two categories: intense and moderate; slight and absent. Localization was divided into left and right, and KRAS status was divided into mutated and wild-type (WT). PFS was calculated using the Kaplan-Meier test. Results: The median PFS of the general population was 8.74 (7.39-11.07) months. The median PFS was 9.86 (7.82-13.41) vs 5.09 (4.43-10.84) months for low and high NLR respectively, with statistical significance (p: 0.01). When the percentage of patients without progression after one year of treatment was analyzed, the difference was 45% vs 14% in favor of NLR < 4 on ≥4, this difference was also statistically significant (p: 0.02). PFS in relation to TILs after one year of follow up was 33% (8.61 months) for moderate-intense infiltrate vs 30% of mild-absent (7.10 months). PFS was 9.79 months for KRAS WT pts vs 7.82 months for mutated KRAS. In terms of location, PFS was 9.79 months for the left colon vs 8.28 months for the right colon. These factors did not have a statistically significant difference. Conclusions: The results of the study show how NLR < 4 is a prognostic factor with a positive impact on PFS. It should be noted that the median survival rates were numerically higher in moderate-intense vs mild-absent TILs, also in KRAS WT vs mutated and in left vs right location. It should also be noted that the possibly there was not a statistically significant difference between them due to the limited number of patients per what we will continue working on in the recruitment and analysis of these patients.

Impact of STK11 mutation on first-line immune checkpoint inhibitor (ICI) outcomes in a real-world KRAS G12C mutant lung adenocarcinoma cohort.

9106 Background: The introduction of KRAS G12C inhibitors into clinical trials has demonstrated promise and may provide a new therapeutic option for patients (pts) harboring KRAS G12C mutations. Recent data has also indicated that immune checkpoint inhibitors (ICI) have shown benefit in KRAS G12C mutant lung adenocarcinoma (LUAD); however, data on the impact of co-occurring STK11 mutations on outcomes are conflicting. We utilized the Guardant INFORM real-world clinical-genomic database to assess the impact of co-occurring STK11 mutations on outcomes in pts with KRAS G12C mutant LUAD treated with a first-line ICI containing regimen. Methods: This retrospective matched cohort observational study was conducted in a nationally representative clinical-genomic database covering over 137,000 pts with comprehensive ctDNA results and associated clinical information. Adult pts with metastatic LUAD who received ≥ 1 dose of first-line anti-PD1/PD-L1 ± chemotherapy and had at least 90 days follow-up after first KRAS G12C detection were included. A cohort of pts without KRAS G12C, including KRAS wildtype pts and pts with other KRAS mutations, were matched 3:1 for age, gender, year of index and baseline comorbidity. Time to next treatment (TTNT), time to discontinuation (TTD), real-world overall survival (rwOS) were compared with vs. without STK11 mutations for both cohorts using cox proportional-hazards model. Results: Among 330 pts in the KRAS G12C cohort, 21% (n = 70) had an STK11 mutation. Among the matched cohort (n = 938), 754 pts were KRAS wildtype, of whom 6% (n = 49) had STK11 mutations. Within the KRAS G12C cohort, pts with STK11 mutations had statistically significant shorter TTNT (hazard ratio [HR] 2.7, 95% confidence internal [CI] 1.8-4.0, p < 0.0001), TTD (HR 1.4, 95% CI 1.0-2.0, p < 0.04) and rwOS (HR 3.2, 95% CI 2.0-5.1, p < 0.0001) than pts without STK11 mutations. Within the matched KRAS wildtype cohort, the differences in TTD (HR 1.4, 95% CI = 1.0-2.0, p = 0.08) and rwOS (HR 1.4, 95% CI = 0.8-2.4, p = 0.3) in patients with vs. without STK11 mutation did not reach statistical significance (Table). Conclusions: This study provides real-world evidence that STK11 co-mutations are associated with worse outcomes among pts with KRAS G12C mutant LUAD treated with first-line ICI. These inferior outcomes indicate a high unmet medical need among LUAD pts harboring co-occurring KRAS G12C and STK11 mutations and demonstrate the need for effective targeted and/or combination therapies in this patient population.[Table: see text]

Comprehensive genomic profiling (CGP) utilizing cell-free DNA (cfDNA) in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).

421 Background: PDAC has a propensity for early systemic dissemination and most pts with primary tumors radiographically confined to the pancreas harbor micro-metastases. cfDNA based CGP offers a non-invasive mechanism to identify actionable genomic targets in PDAC and account for serial clonal evolution in response to therapeutic selection pressure. We interrogated the Foundation Medicine database to characterize cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of pts with PDAC who underwent cfDNA based CGP between May 2016 and February 2020. cfDNA based CGP was done utilizing either the FoundationOne Liquid (F1-Liquid) or the Foundation-ACT (F-ACT) testing platform. Samples were interrogated for exonic and select intronic regions of cancer-related genes for both F1-Liquid (Exons: 70 genes; Select Introns: 7 genes) and F-ACT (Exons: 59 genes; Select Introns: 6 genes). Variant zygosity and somatic/germline status (SGZ) for short variant mutations was computationally predicted without matched normal tissue using an investigational method. A Gaussian Mixture Model (GMM) was used to identify latent molecular classes in samples harboring somatic, pathogenic variants (n=613); the Bayesian Information Criteria (BIC) was used for model selection. Results: We identified 1,009 pts with cfDNA based CGP - median age was 65, 55% were male, and median cfDNA concentration was 24 ng/µL. cfDNA yield had an influence on the detection of somatic alterations (p <0.001). 613/1009 (60.8%) of pts had at least one somatic alteration detected on cfDNA based CGP. TP53 (53.7%), KRAS (40.3%) and CDKN2A (6.5%) were the most frequently altered genes (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [somatic and/or germline BRCA2, ATM, and CHEK2 alterations], were detected in 12.3% (124/1009) pts – 11.4% (46/403) in KRAS mutated pts and 12.9% (78/606) in KRAS wildtype (WT) pts. Fusions were detected only in KRAS WT pts (1.5%, 6/403). Pts with cfDNA based CGP could be classified into 4 latent classes – class 1 ( KRAS - 100%, TP53 - 100% and CDKN2A – 33.3%), class 2 ( KRAS - 65.7%), class 3 ( KRAS – 68.2%, CDKN2A/B – 7.7% ) and class 4 ( KRAS – 38.5%, TP53 - 26.7%). Conclusions: The putative role of cfDNA based CGP in monitoring therapeutic response and clonal evolution in pts with PDAC may be predicated on cfDNA yield. In clinical scenarios where pre-treatment tissue availability is limited, cfDNA based CGP may be have utility in leveraging the predictive value of somatic and/or germline HR-DDR gene alterations. The prognostic and/or predictive relevance of the four latent classes needs validation in clinically annotated data sets. [Table: see text]

Abstract 2254: Variations in the epithelial-mesenchymal transition (EMT) program by non-small cell lung cancer (NSCLC) circulating tumor cells (CTCs) do not influence survival

Abstract Background By definition, CTCs must undergo the EMT to enter the bloodstream where they can be isolated from cancer patients for translational and biological study. Here we examined survival patterns in relation to CTC EMT expression in different molecular subgroups of NSCLC. Methods 125 patients (pts) with advanced treatment-naïve stage IIb-IV NSCLC were prospectively included for CellSearch CTC analysis as part of the Gustave-Roussy MSN study. Patients signed an informed consent for one CellSave tube prior to chemotherapy. Anti-vimentin (vim) antibody was added to the free channel in the CellSearch system for examination of EMT. Association of CTC number with clinical characteristics were assessed using Fisher's exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse progression-free survival (PFS) and overall survival (OS) of vimentin-expression in molecular subgroups of NSCLC. Results 51/125 pts (40.8%) were CTC-positive by CellSearch (≥2 CTC), and 29/125 (23.2%) patient samples contained at least 1 vimentin-positive (+) CTC. 19/76 (25%) adenocarcinomas were KRAS mutated. In the KRAS subgroup, 0/19 patient samples (0%) from pts with mutated KRAS contained vim+ CTC, compared to 17/48 pts (35.4%) with wild-type (WT) KRAS (p = 0.0027). There was also a significantly higher overall number of vim+ CTCs in pts with KRAS WT cancer compared to KRAS mutated cancer (mean 0 vs 1.63, respectively, p = 0.0035). For KRAS WT pts, no survival difference was evident between vim+ and vim- subgroups in terms of PFS or OS. 21/89 adenocarcinomas were EGFR mutated (23.6%). In this subgroup, statistically higher numbers of EGFR mutated pts with both vim+ and total CTCs were observed compared to EGFR WT pts (vim+ CTC: 9/21 EGFR mutated vs 9/56 EGFR WT, p = 0.0134; total CTC: 12/21 EGFR mutated vs 18/56 EGFR WT, p = 0.0451). Similarly, there was a significantly higher overall number of vim+ CTCs in pts with EGFR mutated cancer compared to pts with EGFR WT cancer (mean 1.24 vs 0.91, respectively, p = 0.0189), but no PFS or OS difference was evident between vim+ and vim- subgroups in EGFR mutated pts. 14/71 (19.7%) adenocarcinomas were ALK rearranged, with further results pending. Conclusions At baseline stage IIIb-IV disease, there are statistically fewer vim+ CTCs (and pts with vim+ CTCs) in KRAS mutated NSCLC, while vim+ CTC (and vim+ CTC pts) are statistically higher in EGFR mutated NSCLC. Despite this differential CTC vimentin expression between molecular subgroups, no PFS or OS difference is evident between vim+ and vim- patients. This biological variation coupled to a lack of overall clinical impact favours the hypothesis that each individual CTC is a highly plastic cell that can cover a range of EMT expression. Citation Format: Colin R. Lindsay, Vincent Faugeroux, Emma Pailler, Maria-Virginia Bluthgen, Chloé Pannet, Maud Ngo-Camus, Guillaume Bescher, Fanny Billiot, Jordi Remon, Philippe Vielh, David Planchard, Jean-Charles Soria, Benjamin Besse, Françoise Farace. Variations in the epithelial-mesenchymal transition (EMT) program by non-small cell lung cancer (NSCLC) circulating tumor cells (CTCs) do not influence survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2254.

Prospective biomarker validation trial evaluating the prognostic role of the combined expression of phospho-insulin growth factor receptor-1 and matrilysin in KRAS (exon 2) wild-type (WT) metastatic colorectal cancer (mCRC) patients treated with FOLFOX-6 plus panitumumab as first-line therapy [PULSE trial (GEMCAD 09-03)

583 Background: Matrilysin can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Matrilysin per se has shown poor prognosis in mCRC and the co-expression of matrilysin and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS refractory patients (pts) treated with anti-EGFR in retrospective analyses. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX plus panitumumab in first-line therapy to validate those findings. Methods: Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++/+++) and > 70% expression for both matrilysin and p-IGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (two-sided p< 0.05). Results: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 78 pts met inclusion criteria (42 non-DP and 36 DP). Median follow-up was 23 months. There were no differences in baseline characteristics [age, sex, liver metastases, lactate dehydrogenase (LDH) levels, performance status and BRAF mutational status] between both groups. There were no differences in the number of FOLFOX-6 and panitumumab cycles received. Cutaneous toxicity was more frequent in DP pts (p = 0.035). Response rate was 80.5% in non-DP and 72.2% in DP patients (p = 0.37). Median PFS (95% CI) was 7.4 months (95%CI 5.2-13.3) in non-DP and 9.6 months (95% CI 6.7-17.5, p = 0.15) in DP patients. Median overall survival was 19.8 months (11.5-26.3) in non-DP pts and 39.1 months (26-NE, p = 0.071) in DP pts. Adjusted HR for PFS was 0.68 (95% CI 0.41-1.12). Adjusted analysis for OS was 0.50 (95% CI 0.27-0.90). Conclusions: We found that co-expression of matrilysin and pIGF-1R is a novel strong prognostic biomarker of survival benefit in mCRC KRAS WT pts treated in first-line with FOLFOX-6 plus panitumumab. Clinical trial information: NCT01288339.

Improving access to molecularly defined clinical trials for patients with colorectal cancer: The EORTC SPECTAcolor platform.

575 Background: Molecular diagnostics can identify subgroups of colorectal and other cancers that are relevant for the mode of action of new anti-cancer agents. The efficient, GCP-conform and quality assured molecular screening to identify potential study patients is one of the major challenges for targeted drug development. The EORTC has implemented a new collaborative molecular screening platform in order to facilitate these next generation trials. Methods: SPECTAcolor (Screening Patients for Efficient Clinical Trial Access in advanced colorectal cancer) is a pan European network of institutions collaborating in centralized, high-throughput screening of tumor material from patients with colorectal cancer. After informed written consent, patients are screened for molecular alterations. Molecularly annotated patients can be offered so called “downstream” clinical trials. Results: Launched in September 2013, SPECTAcolor is now initiated in 19 clinical centers in 9 countries. As of 12 September 2014, 406 patients were enrolled exceeding the expected accrual target of 300 patients in the first year. Of these 406 patients, 293 patients had their tumor block shipped to the central biobank at the Dresden University Hospital for central quality and pathological review, and core analyses. Tumor samples are being additionally analyzed using next generation sequencing for 360 key cancer alterations in cooperation with the Sanger Institute (Cambridge, UK). In the first year, the blocks were analyzed for 5 baseline biomarkers. KRAS was wild type for exon 2, 3 and 4 in 151/284 pts (53%) and mutated 133 pts (47%; 114 pts in exon 2 (40%), 8 pts in exon 3, and 11 pts in exon 4). NRAS was tested in KRAS wild type pts only; mutations were found in 14 pts (4.9%; 6 pts in exon 2 and 8 pts in exon 3). BRAF mutations, all in exon 15, were found in 18 pts (7%). PI3K mutations occurred in 41 pts (15%; 13 in exon 20 and 28 in exon 9). IHC staining was showing deficient mismatch repair in 16 patients. Conclusions: SPECTAcolor is the first pan-European and EORTC screening platform. Its successful implementation proves that a logistically complex infrastructure to run next generation trials in a multinational setting is feasible.

Amphiregulin (AREG) expression and response to first-line panitumumab (pmab) plus FOLFIRI in metastatic colorectal cancer (mCRC).

731 Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]

O1-9-2 - Tumor Genomic Profiling of Nsclc From the Phase III Trial of First-Line S-1/Cbdca Versus Paclitaxel/Cbdca (Wjog6611Ltr)

Background: Over the last decade, substantial advances have been made in developing genotype-based target therapies for advanced NSCLC. There is an increasing need to develop high-throughput genotyping tests to evaluate larger number genetic abnormalities.Method: Archived FFPE specimens obtained at the diagnosis were available for 304 (53.9%) of the 564 patients (Pts) who were enrolled in LETS study. With the use of Sequenom's MassARRAY system, we conducted high-throughput genotyping including somatic mutations and gene fusions (ALK, ROS1 and RET). We also evaluated MET amplification by FISH.Results: A somatic mutation in at least one was identified in 105 (48%) of the 217 pts with non-squamous cell carcinoma (SCC) and 26 (45%) of the 58 pts with SCC. Overall, we identified EGFR mutations in 46 patients (17%), TP53 mutations in 30 (11%), STK11 mutations in 27 (9.8%), MET mutations in 21 (7.6%), KRAS mutations in 17 (6.2%), PIK3CA mutations in 6 (2.2%), BRAF and NRAS mutations in each 3 (1.1%), and DDR2, ERBB2, NRF2 and PTEN mutations in each one patient (0.4%). The median overall survival (OS) of EGFR mutation-positive pts was significantly longer than that of pts without EGFR mutations (23.7 v 12.6 months; P = 0.004). Conversely, pts whose tumors had KRAS mutations had a significantly shorter survival than KRAS-wild type pts (9.9 v 15.3 months; P = 0.04). LungFusion panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and RET fusion in one case (0.4%), and these three rearrangements were mutually exclusive. Among five ROS1-fusion positive patients, two patients concomitantly had KRAS mutations, and one patient had EGFRL858R and PIK3CAE542K. Nine out of 229 advanced NSCLC pts (3.9%) were identified as having de novo MET amplification.Conclusions: MassARRAY-based multiplex genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE NSCLC tissues obtained from advanced NSCLC.

O-0009 - Quantitative Analysis of the Impact of Deepness of Response on Post-Progression Survival Time Following First-Line Treatment in Patients with Mcrc

Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy with or without monoclonal antibodies is prognostic for progression-free survival (PFS) and overall survival (OS). The ‘Deepness of response (DpR)’ concept aims to relate tumor shrinkage to post-progression survival (PPS). If tumor shrinkage does take place, DpR is the percentage of tumor shrinkage observed at the nadir compared with baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can be used to quantify the tumor load. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows the prediction of PPS time for an individual patient based on DpR. Methods: Based on the data from the randomized CRYSTAL and OPUS trials, four treatment regimens (FOLFIRI +/- cetuximab and FOLFOX4 +/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. A Spearman correlation was used to study the relationship between DpR and PPS for KRAS wild-type pts with progressive disease. Results: Results are reported using LD-based measures for 841 pts with KRAS wild-type tumors and imaging data: 663 from the CRYSTAL study and 178 from the OPUS study. The 348 pts treated with FOLFIRI alone had a median DpR of 33.3% (interquartile range [IR]: 8.0%, 58.0%) while the 315 pts treated with FOLFIRI + cetuximab had a significantly higher median DpR of 50.9% (IR: 18.4%, 78.6%), p < 0.0001. The 96 pts treated with FOLFOX4 alone had a median DpR of 30.7% (IR: 4.0%, 55.9%) and the 82 pts treated with FOLFOX4 + cetuximab had a significantly higher median DpR of 57.9% (IR: 24.0%, 92.9%), p = 0.0008. Correlation between DpR and PPS for pts with documented disease progression was statistically significant in each of the two treatment groups and for both LD-based and volume-based measurements (p < 0.0001 for the CRYSTAL study and p < 0.005 for the OPUS study). The hazard ratios show a higher DpR to significantly favor a longer PPS time across the two studies and both treatment groups for both LD- and volume-based measurements. Conclusion: Our results emphasize the value of DpR as a new efficacy outcome measure for clinical trials. Furthermore the addition of cetuximab to chemotherapy was shown to significantly increase DpR with the prolongation of PPS and thus OS.

Association of KRAS mutation with worse recurrence-free survival and site of metastatic progression after resection of hepatic colorectal metastases.

3609 Background: There are conflicting results regarding the influence of KRAS mutation status and outcome in patients (pts) with colorectal cancer. A recent report suggested worse outcome in KRAS mutated (MUT) pts who underwent resection of hepatic metastases (Karagkounis et al, ASCO 2012). Methods: Recurrence patterns and survival were evaluated in 169 patients who had undergone resection of liver metastases, then received adjuvant hepatic arterial infusion and systemic chemotherapy, and for whom KRAS data were available. Kaplan-Meier methods were used to estimate recurrence free survival (RFS) and overall survival (OS). Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adjuvant therapy to bone, brain, lung and liver metastases separately. Mutations in KRAS (codons 12, 13) were detected using the iPLEX assay (Sequenom, Inc). Results: Median follow-up for the entire cohort was 38.8 months. 118 were KRAS wildtype (WT), and 51 were KRAS MUT (45 G12, 5 G13, 1 K117N). The 3 year RFS was 48% [95%CI: 37-58%] for KRAS WT pts and 30% [15-44%] for MUT pts (p&lt;0.01). OS at 3 years was 96% [88-98%] for KRAS WT and 80% [61-90%] for MUT pts (p=0.08). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in Table 1. The cumulative incidence of metastases to bone at 2 years was 0% and 13.7% in KRAS WT versus MUT pts (p&lt;0.01), to brain 0% versus 4.6% for KRAS WT versus MUT (p=0.05), and to lung 27% versus 47.5% in KRAS WT versus MUT pts (p&lt;0.01). Conclusions: In pts who have had liver resection followed by adjuvant therapy, those with KRAS MUT have a worse RFS and seemingly worse OS than those who are KRAS WT. Also, patients with KRAS MUT appear more likely to develop bone, brain, and lung metastases. Further investigation of a larger number of patients is warranted. [Table: see text]

Clinical impact of first response evaluation (FRE) in metastatic colorectal cancer (mCRC) patients (pts) treated with a cetuximab-based regimen (C-R): Results of a mono-institutional experience.

e14717 Background: Some reports suggest positive impact from early tumor shrinkage in progression-free survival (PFS) and overall survival (OS) in mCRC pts receiving C-R. The aim was to evaluate the clinical impact of FRE in mCRC pts treated with a C-R in first-line (1st-L) or after 1st-L. Methods: Between May 2004 and Dec. 2012, 73 pts referred to our institution. The FRE was assessed 8-10 wks after the start of treatment by a CT-scan according to RECIST criteria 1.0. At the time of FRE, pts who achieved CR/PR were considered as responders (resp), and SD/PD as non-responders (non-resp). Were included KRAS wild-type (KRAS-wt) and KRAS undefined tumors (KRAS-ud). PFS and OS are reported in months. Results: Pt characteristics: 51M (70%) and 22F (30%); median age 62(27-80) yrs; 59 colon (80.8%) and 14 rectum (19.2%); median number of metastatic sites 2 (1-5); synchronous mts 47 (64.4%), metachronous mts 26 (35.6%); 46 (63%) KRAS-wt, 27 (37%) KRAS-ud. Twenty-nine (39.7%) pts were treated with C-R in 1st-L (all KRAS-wt), and 44 (60.3%) after 1st-L (17 KRAS-wt, 27 KRAS-ud). C was combined with FOLFIRI in 36 (49.3%) pts, irinotecan in 36 (49.3%), and was alone 1 (1.4%). At the time of FRE 26(35.6%) pts were resp: 13 1st-L and 13 after 1st-L; 47 (64.4%) were non-resp: 16 (34%) 1st-L and 31 (66%) in after 1st-L. In pts treated as 1st-L, the PFS in resp vs non-resp was: 13 (95% CI 6-20) vs 5 (95% CI 4-5) (p=0.03); the OS was: 23 (95% CI 11-34) vs 11 (95% CI 9-13) (p=0.11). In pts treated after 1st-L the PFS in resp vs non-resp was: 13 (95% CI 8-18) vs 5 (95% CI 0.4-9) (p&lt; 0.0001); the OS was: 17 (95% CI 12-21) vs 12 (95% CI 6-19) (p 0.67). In the KRAS-wt pts the PFS in resp vs non-resp was: 13 (95% CI 11-15) vs 5 (95% CI 4-6) (p 0.00); the OS was 23 (95% CI 16-30) vs 11 (95% CI 8-14) (p 0.02). In the KRAS-ud pts the PFS, in resp vs non-resp was: 9 (95% CI 0-20) vs 3 (95% CI 0-8) (p 0.00), the OS was: 18 (95% CI 1-36) vs 13 (95% CI 10-15) (p 0.03). A Cox regression model, including: sex, age, KRAS, line of therapy, FRE, skin rash grade, shows that the FRE was the main predictor of PFS (p&lt;0.0001) and OS (p=0.011). Conclusions: The FRE seems to predict the clinical outcome in pts receiving C-R as 1st-L or after 1st-L.

Influence of KRAS mutation on recurrence patterns in patients undergoing hepatic resection of colorectal metastases.

398 Background: There have been conflicting results about whether KRAS mutation influences outcome in patients (pts) with colorectal cancer. In pts who underwent liver resection, Karagkounis reported a worse recurrence and survival in KRAS mutated (MUT) patients (ASCO 2012, abs 3616). Methods: In 105 pts who underwent liver resection and received adjuvant (adj) hepatic arterial infusion and systemic chemotherapy and in whom KRAS data was available, we evaluated recurrence patterns and survival. Correlation between KRAS and clinical factors such as prior chemotherapy, post operative CEA, clinical risk score, and stage at diagnosis was evaluated using Fisher’s exact test and the Wilcoxon rank sum test. Kaplan-Meier methods were used to estimate median overall recurrence free survival (RFS) and overall survival (OS) at 4 years. Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adj therapy to bone, brain, lung and liver metastases separately. Results: Of 105 patients, 76 were KRAS wildtype (WT), and 29 were KRAS MUT (26-G12 and 3-G13). The median RFS was 26 months for KRAS WT pts and 15 months for KRAS MUT pts (p=0.08). OS at 4 years was 88% [95% CI: 78%-94%] for KRAS WT and 78% [95% CI: 57%-90%] for KRAS MUT pts (p= 0.15). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in the Table. The cumulative incidence of bone and brain metastases at 2 years was 0% and 0% in KRAS WT pts versus 16.4% [95% CI: 1.1%-31.7%] and 4.7% [95% CI: 0%-14.1%] in KRAS MUT pts (Table). There was no association between clinical factors and KRAS status. Conclusions: KRAS MUT pts appeared to have worse OS and RFS, although we were unable to show a significant difference between KRAS WT and MUT for OS and RFS. In addition, cumulative incidence of bone and brain metastases at 2 years appeared to be higher for KRAS MUT pts as compared to WT pts. Results are based on small sample size and further investigation is needed. [Table: see text]

565P - Bevacizumab (BEV) + Chemotherapy (CT) Beyond First Progression in Patients (PTS) with Metastatic Colorectal Cancer (MCRC) Previously Treated with Bev-Based Therapy: Overall Survival Subgroup Findings from ML18147

ABSTRACT Background ML18147 evaluated the benefit of continuing BEV + standard CT as second-line (2L) treatment for pts with mCRC progressing after first-line (1L) BEV-containing therapy. Here we report results of pre-specified subgroup and exploratory KRAS mutation analyses. Methods Pts with unresectable, histologically confirmed mCRC progressing within 3 mo after discontinuing 1L BEV were randomised to 2L fluoropyrimidine + oxaliplatin or irinotecan (crossed over from 1L) ± BEV (2.5 mg/kg/wk equivalent). The primary endpoint was overall survival (OS). Subgroup analyses for OS were performed using the same statistical method as for the primary analysis. Results 409 pts were randomised to BEV + CT and 411 to CT (1 pt not treated). Median OS was 11.2 mo for BEV + CT vs 9.8 mo for CT (unstratified HR = 0.81; 95% CI 0.69–0.94; p = 0.0062). Subgroup analyses for OS were generally consistent with the overall population (Table). While the treatment effect in female pts appeared to be lower, the treatment-gender interaction test was not statistically significant. Category Subgroup N HR for OS 95% CI All All 819 0.81 0.69–0.94 Gender Female Male 294 525 0.99 0.73 0.77–1.28 0.60–0.88 Age ≥ 65 y 458 361 0.79 0.83 0.65–0.98 0.66–1.04 ECOG PS 0 ≥ 1 357 458 0.74 0.87 0.59–0.94 0.71–1.06 First-line PFS ≤9 mo > 9 mo 449 369 0.89 0.73 0.73–1.09 0.58–0.92 First-line chemotherapy Oxaliplatin-based Irinotecan-based 343 476 0.79 0.82 0.62–1.00 0.67–1.00 Time from last BEV dose ≤42 d > 42 d 630 189 0.82 0.76 0.69–0.97 0.55–1.06 Liver metastases only No Yes 592 226 0.81 0.79 0.67–0.97 0.59–1.05 No. of organs with metastasis 1 > 1 307 511 0.83 0.77 0.64–1.08 0.64–0.94 KRAS mutation data were available from an exploratory analysis in 616 pts (75%); median OS for KRAS wild-type (WT) pts was 15.4 mo for BEV + CT vs 11.1 mo for CT (HR = 0.69, 95% CI 0.53–0.90; p = 0.0052); in KRAS mutant (MT) pts median OS was 10.4 vs 10.0 mo, respectively (HR = 0.92; 95% CI 0.71–1.18; p = 0.4969). Median PFS for KRAS WT pts was 6.4 mo for BEV + CT vs 4.5 mo for CT (HR = 0.61; 95% CI 0.49–0.77; p Conclusions ML18147 showed that BEV + CT continued beyond progression significantly improves survival vs CT alone. Findings from the subgroup analyses for OS were generally consistent with the overall population. Disclosure J.M. Vieitez de Prado: Involved in corporate-sponsored trials for Roche. D. Arnold: Consultant / Advisory Board: Roche. Honoraria: Roche. Research funding: Roche. R. Greil: Honoraria: Roche Research support: Roche. E.J.D. Van Cutsem: Research funding: Roche. R. von Moos: Consultant/advisory board: Roche. Honoraria: Roche. Research funding: Roche. J. Bennouna: Consultant / advisory board: Roche. Honoraria: Roche. I. Reyes-Rivera: Employed by Genentech Inc. B. Bendahmane: Employed by F. Hoffmann-La Roche. S. Kubicka: Consultant / advisory board: Roche. Honoraria: Roche. All other authors have declared no conflicts of interest.

520O - Adjuvant Folfox4 Plus or Minus Cetuximab (CMAB) in Patients (PTS) with Kras Mutant (MKRAS) Resected Stage III Colon Cancer (CC). Results from the PETACC8 Intergroup Trial

ABSTRACT Background FOLFOX4 is standard adjuvant therapy for resected stage III CC. PETACC 8 assessed the potential benefit of Cmab added to FOLFOX4 in resected stage III CC. Initially PETACC 8 enrolled pts regardless of KRAS status; here we report efficacy and tolerability results in mKRAS pts prior to an amendment restricting enrolment to pts with KRAS wild-type tumors. Methods Pts with informed consent were randomized 28-56 days following resection to 12 biweekly cycles of oxaliplatin 85 mg/m2 d1, with leucovorin 200 mg/m2, 5FU 400 mg/m2 bolus IV, then 22-hr IV 5FU 600 mg/m2 on d1and2 (FOLFOX4), without (arm A) or with Cmab (arm B) 250 mg/m2 weekly ( 400 mg/m2, cycle1). Tumors were centrally tested for KRAS. This analysis focuses on pts with mKRAS CC. The primary endpoint was disease free survival (DFS) time. Secondary endpoints included overall survival (OS), treatment compliance and toxicity. Subgroup analysis were performed. Results 742 pts with mKRAS CC were enrolled prior to the restriction to pts with KRASwild-type tumors (Arm A, 374; Arm B, 368). Median follow-up is 45.4 months. No difference was seen between the arms for DFS (HR 1.06, 95% CI 0.82-1.37; p = 0.65). 3-yr DFS was 71.0% (95% CI 66.0-75.3) in Arm A and 70.7% (95% CI 65.6-75.1) in Arm B. No statistical benefit of Cmab was observed in any of the subgroups analysed. The frequency of any AE grade ≥ 3 was significantly increased in Arm B (68.4% Arm A vs 81.0% Arm B; RR: 1.18, 95% CI 1.09-1.29). Diarrhea, asthenia, mucositis, skin disorders (grade ≥ 3) and failure to complete 12 cycles were also significantly higher in Arm B. Conclusions The analysis of this randomized phase III trial has not shown a benefit for adding cetuximab to FOLFOX4 in patients with resected stage III mKRAS CC with global results very close to those observed in KRAS wild type pts. Supported by Merck-Serono, Sanofi-Aventis. Disclosure G. Folprecht: - Honoraries, for lectures and advisory boards from Merck KGaA and Bristol Mayers Squibb. -study grant from Merck KGaA -involved in clinical trials with Imclone and Merck KGaA J. Taieb: advisory board and consutancy for Sanofi Aventis and Merck Serono. All other authors have declared no conflicts of interest.

Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer: the choice and schedule of fluoropyrimidine matters

Cetuximab, a monoclonal antibody against the epidermal growth factor receptor, inconsistently improves response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced colorectal cancer patients with K-ras wild-type (WT) tumors. We performed a meta-analysis of four trials where K-ras WT Pts received a fluoropyrimidine (infusional vs. bolus 5-fluorouracil (5-FU) vs. capecitabine) and oxaliplatin or irinotecan with and without cetuximab (CRYSTAL, OPUS, COIN and NORDIC VII trials) and two trials, where K-ras WT and mutant patients received cetuximab and a fluoropyrimidine (capecitabine in a German AIO study and infusional 5-FU in the CECOG study) with oxaliplatin versus irinotecan. We sought to determine whether the choice of fluoropyrimidine or of oxaliplatin versus irinotecan affects the response to cetuximab. Meta-analysis was performed in the context of a mixed effects model with a random effect for each study. Only patients treated with infusional 5-FU-based chemotherapy derived benefit from cetuximab. Relative to infusional 5-FU, patients treated with capecitabine/bolus 5-FU-based doublet chemotherapy had a 42% (95% CI 21-58%; p<0.001) decrease in response probability and a 52% (95% CI 20-93%; p<0.001) and 33% (95% CI 7-65%; p=0.012) increase, respectively, in risk of progression and death. The choice of oxaliplatin or irinotecan did not affect benefit from cetuximab. The lack of benefit for cetuximab with capecitabine/bolus 5-FU regimens is unexpected. Cetuximab should only be used with infusional 5-FU regimens in the first-line treatment of K-ras WT colorectal cancer patients. Further study is urgently needed to elucidate the basis of this observation.

Survival outcome segregated by KRAS mutation status in newly diagnosed stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with first-line chemotherapy.

7595 Background: KRAS mutations (MT) form a distinct subset of NSCLC, generally considered to have poor prognosis. Although KRAS MT is a well-establised prognostic and predictive marker in colorectal cancer, its role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not respond well to epidermal growth factor receptor (EGFR) directed tyrosine kinase inhibitor therapy, but little is known about the ability of KRAS MT to predict outcome after first-line chemotherapy in newly diagnosed advanced or recurrent NSCLC. Methods: We analyzed outcomes of consecutive pts with newly identified Stage IV non- squamous NSCLC treated at University of Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared survival based on KRAS status [MT vs wild type (WT)] using chi square, Kaplan-Meier methods, and Cox regression models. Results: Of 106 consecutive new pts with Stage IV non squamous NSCLC treated at Penn, 49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median age of all 49 pts was 61 years; 83% were Caucasian, 45% male and 60% had a &gt;10 pack year smoking history. Median duration of follow up is 16.4 mos. Majority of pts (92%) had adenocarcinoma histology. Most pts (88%) had ECOG PS 0-1 at presentation. Forty three pts received first line platinum-based combination chemotherapy (platinum and pemetrexed in 31 pts). KRAS MT was associated with smoking (p=0.04), but not with gender or age. Overall survival (OS) of pts with KRAS MT was similar to KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI 0.57-2.67)]. Univariate analyses demonstrated superior OS among women compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort. Conclusions: In our population of stage IV non squamous NSCLC, pts with KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly higher in KRAS WT pts, but this may have been confounded by the inclusion of 6 EGFR MT pts in this cohort. The potential prognostic or predictive role of KRAS MT in NSCLC pts undergoing chemotherapy requires further prospective study.