Chemorefractory Colorectal Cancer Research Articles

Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer.

In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75mg/m(2) for 21 consecutive days every 4weeks, for up to sixcycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16% (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p < 0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.

Abstract LB-119: MGMT immunohistochemistry (IHC) improves patients’ selection for temozolomide (TMZ) treatment in advanced chemorefractory MGMT-methylated colorectal cancer

Abstract Background: We showed that standard dose TMZ (150 mg/mq/day day1-5q28) is tolerable and active in 32 heavily pre-treated patients with advanced CRC and MGMT promoter methylation (Pietrantonio et al., Ann Oncol 2014). In a subsequent study, we included 32 pts treated with dose-dense TMZ (75 mg/mq/day day 1-21q28, for up to 6 cycles or until progression/unacceptable toxicity). Additional predictive markers are needed for improved selection of patients for TMZ therapy in metastatic CRC. Retained MGMT expression by IHC was proposed as marker for negative selection of pts with brain tumors. We conducted a retrospective analysis to assess MGMT expression in our 2 studies and to correlate this with the outcomes. Methods: All 64 patients included in the 2 studies were defined as MGMT methylation-positive according to methylation-specific PCR. A total of 40 patients had tissue available for IHC. Expression of nuclear MGMT protein was defined scored semiquantitatively according to extension and intensity. Using ROC analysis, IHC score &amp;lt;4 was considered as MGMT-low expression vs. IHC score 4-12 as MGMT-high. Extended RAS-BRAF mutations were assessed by Sanger sequencing. Results: Herein, we report for the first time the results of the dose-dense TMZ study. We obtained 4 confirmed partial responses and 2 stable disease, accounting for a response rate of 12% and a clinical benefit of 18%. Median PFS was 1.8 months. OS data are not mature. Thus, the results are comparable to those obtained in the previous study. MGMT-low expression was found in 15 (38%) samples and MGMT-high in 25 (62%). RAS-BRAF mutations were found in 28 (70%) pts and were not correlated with MGMT expression (p = 1). Response rate was significantly higher in patients with MGMT-low (53%) vs. those with MGMT-high (p&amp;lt;0.0001). Progression-free survival was significantly longer in MGMT-low vs. MGMT-high(5 vs. 2.3 months; p = 0.001). Further analyses are ongoing to validate MGMT IHC as a biomarker and to correlate it with quantitative gene methylation analysis. Conclusions: In this translational study on MGMT methylated CRC, absence of MGMT expression was significantly correlated with tumor response and benefit from TMZ treatment. Citation Format: Filippo De Braud, Filippo Pietrantonio, Maria Di Bartolomeo, Katia Fiorella Dotti, Claudia Maggi, Roberto Iacovelli, Marta Caporale, Rosa Berenato, Federica Perrone, Elena Tamborini, Alessio Pellegrinelli, Stefano Federici, Fabrizio Festinese, Giuseppe Pelosi, Ilaria Bossi, Paola Valentina Consonni, Susanna Maggi, Massimo Milione. MGMT immunohistochemistry (IHC) improves patients’ selection for temozolomide (TMZ) treatment in advanced chemorefractory MGMT-methylated colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-119. doi:10.1158/1538-7445.AM2015-LB-119

Radioembolization as a Salvage Therapy for Heavily Pretreated Patients With Colorectal Cancer Liver Metastases: Factors That Affect Outcomes

BackgroundIn this study we assessed the efficacy and factors that affect outcomes of radioembolization (RE) using yttrium-90 resin microspheres in patients with unresectable and chemorefractory colorectal cancer liver metastases (CLM). Patients and MethodsAfter an institutional review board waiver of approval, a review of a Health Insurance Portability and Accountability Act-registered, prospectively created and maintained database was performed. Data on patient demographic and disease characteristics, RE treatment parameters, and additional treatments were evaluated for significance in predicting overall survival (OS) and liver progression-free survival (LPFS). Complications were evaluated according to the National Cancer Institute Common Terminology Criteria for adverse events. ResultsFrom September 2009 to September 2013, 53 patients underwent RE at a median of 35 months after CLM diagnosis. Median OS was 12.7 months. Multivariate analysis showed that carcinoembryonic antigen levels at the time of RE ≥ 90 ng/mL (P = .004) and microscopic lymphovascular invasion of the primary (P = .002) were independent predictors of decreased OS. Median LPFS was 4.7 months. At 4 to 8 and 12 to 16 weeks after RE, most patients (80% and 61%, respectively) according to Response Evaluation Criteria in Solid Tumors (RECIST) had stable disease; additional evaluation using PET Response Criteria in Solid Tumors (PERCIST) led to reclassification in 77% of these cases (response or progression). No deaths were noted within the first 30 days. Within the first 90 days after RE, 4 patients (8%) developed liver failure and 5 patients (9%) died, all with evidence of disease progression. ConclusionRE in the salvage setting was well-tolerated, and permitted the administration of additional therapies and led to a median OS of 12.7 months. Evaluation using PERCIST was more likely than RECIST to document response or progression compared with the baseline assessment before RE.

Uracil/tegafur as a possible salvage therapy in chemo-refractory colorectal cancer patients: a single institutional retrospective study.

Aim of the studyOur aim was to determine the activity and toxicity of uracil/tegafur and leucovorin combination in metastatic colorectal cancer (mCRC) patients who have progressed with all currently active agents.Material and methodsThis study was a retrospective analysis of 50 mCRC patients who had previously failed to respond to all available chemotherapeutics and who received subsequent treatment with uracil/tegafur 250 mg/m2 d1–5 in combination with leucovorin 90 mg/day, d1–5 followed by two days’ rest.ResultsThe median age of the patients was 60 years. Most of them (60%) were male. Bevacizumab was used in 65% and cetuximab in 55% of the patients. Thirty-nine patients (78%) were treated with uracil/tegafur in the fourth line setting. The median treatment duration was 4.2 months (range, 2–24 months). The objective response rate and the disease control rate were 4% and 34%, respectively. Median progression-free survival was 4.1 months (95% CI, 3.6–4.6 months) and overall survival was 6.6 months (95% CI, 4.5–8.6 months). Grade 3 or 4 toxicity was seen in 20% (n = 10) of the patients while 60% (n = 6) of them required dose reductions.ConclusionsThis retrospective data show that uracil/tegafur may be considered in heavily pretreated mCRC patients because of its activity, lower toxicity, and feasibility.

Is Yttrium-90 Radioembolization a Viable Treatment Option for Unresectable, Chemorefractory Colorectal Cancer Liver Metastases? A Large Single-Center Experience of 302 Patients

We report the largest series to date on the safety and efficacy of yttrium-90 (90Y) radioembolization for the treatment of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM). A total of 302 patients underwent resin-based 90Y radioembolization for unresectable, chemorefractory CRCLM between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the response criteria in solid tumors criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method, and potential prognostic variables were identified on univariate and multivariate analysis. Median follow-up in the complete cohort was 7.2 months (range 0.2-72.8), and the median survival after 90Y radioembolization was 10.5 months with a 24-month survival of 21%. On imaging follow-up of 293 patients who were followed up beyond 2 months, complete response to treatment was observed in 2 patients (1%), partial response in 111 (38%), stable disease in 96 (33%), and progressive disease in 84 (29%). Four factors were independently associated with a poorer prognosis: extensive tumor volume, number of previous lines of chemotherapy, poor radiological response to treatment, and low preoperative hemoglobin. One hundred fifteen (38%) developed clinical toxicity after treatment; most complications were minor (grade I/II) and resolved without active intervention. 90Y radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM.

P1-12-2 - A Retrospective Analysis of the Efficacy and Safety of Regorafenib in Patients with Chemo-Refractory Colorectal Cancer

Regoragenib is a novel oral multi-kinase inhibitor, which was approved by Japanese Ministry of Health, Labor and Welfare in March 2013. The purpose of this study was to verify the efficacy and safety of regorafenib in Japanese patients with colorectal cancer. We retrospectively analyzed 14 patients with chemo-refractory colorectal cancer, who had taken regorafenib orally in Tohoku University Hospital between June 1, 2013 and January 30, 2014. Mean age of the patients was 62.4 years old and 8 patients were male. Twelve patients had colon cancer and 2 patients had rectal cancer. Ten patients had liver metastasis, 3 had abdominal dissemination. Nine patients (64%) had KRAS mutation. Median time to failure was 48 days and the mean number of therapeutic course was 2.8. Among the patients who had measurable lesions, the best overall response was stable disease in 3 patients, and progressive disease in 3. Because of adverse events, the therapy was discontinued in 4 patients before the first response evaluation. Four patients had not yet had the first evaluation for the response until January 1, 2014. Major adverse events (≥ grade 2) were observed in 11 patients (79%), including elevation of liver enzyme (n = 8), hand-foot skin reaction (n = 7), and anorexia (n = 5). Severe adverse events (≥ grade 3) were seen in 8 patients (57%), including elevation of liver enzyme (n = 5), hand-foot skin reaction (n = 1), fatigue (n = 1), hypertension (n = 1), anorexia (n = 1), aspiration (n = 1) and rhabdomyolysis (n = 1). These treatment effects and toxic profiles by regorafenib treatment were consistent with those reported in previous other studies. In conclusion, our data support the notion that regorafenib is one of well-tolerated treatment option for chemo-refractory, progressive or recurrent colorectal cancer in Japanse populations as well. We also report a case of rhabdomyolysis which had never been reported as an adverse event of regorafenib therapy before its approval.

Heterogeneous EGFR gene copy number increase is common in colorectal cancer and defines response to anti-EGFR therapy.

Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12–0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC.

P-0267 - Dose-Dense Temozolomide (TMZ) in Patients with Advanced Chemorefractory Colorectal Cancer (CRC) and Mgmt Promoter Methylation

Introduction: In a previous phase II study, we showed that TMZ is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation, particularly in the RAS-BRAF wild-type subgroup (Pietrantonio et al., Ann Oncol 2014). In fact, MAPK signaling may enhance MGMT activity and RAS-BRAF mutations may drive cellular resistance to standard dose TMZ. However, dose-dense TMZ results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor (Tolcher et al., BJC 2003).

Efficacy of yttrium-90 (Y90) radioembolization in patients with chemorefractory colorectal cancer (CRC) liver metastasis: Results of Bologna study.

e14547 Background: Y90 radioembolisation is a promising treatment for chemorefractory CRC liver metastasis patients (pts). This pilot study investigated in a single institution the safety/efficacy ...

Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation

No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P=0.004). TP53 status had no influence on the primary end point. Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.

A systematic review on the safety and efficacy of yttrium-90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases

The management of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM) is a clinical dilemma. Yttrium-90 (Y90) radioembolization is a potentially safe and effective treatment for patients with CRCLM who have failed conventional chemotherapy regimens. A systematic review of clinical studies before November 2012 was performed to examine the radiological response, overall survival and progression-free survival of patients who underwent Y90 radioembolization of unresectable CRCLM refractory to systemic therapy. The secondary objectives were to evaluate the safety profile of this treatment and identify prognostic factors for overall survival. Twenty studies comprising 979 patients were examined. Patients had failed a median of 3 lines of chemotherapy (range 2-5). After treatment, the average reported value of patients with complete radiological response, partial response and stable disease was 0% (range 0-6%), 31% (range 0-73%) and 40.5% (range 17-76%), respectively. The median time to intra-hepatic progression was 9 months (range 6-16). The median overall survival was 12 months (range 8.3-36). The overall acute toxicity rate ranged from 11 to 100% (median 40.5 %). Most cases of acute toxicity were mild (Grade I or II) (median 39%; range 7-100%) which resolved without intervention. The number of previous lines of chemotherapy (≥ 3), poor radiological response to treatment, extra-hepatic disease and extensive liver disease (≥ 25%) were the factors most commonly associated with poorer overall survival. Y90 radioembolization is a safe and effective treatment of CRCLM in the salvage setting and should be more widely utilized.

Phase I Trial of Selective Internal Radiation Therapy for Chemorefractory Colorectal Cancer Liver Metastases Progressing After Hepatic Arterial Pump and Systemic Chemotherapy

IntroductionThis prospective study assessed the safety and outcomes of selective internal radiation therapy (SIRT) using yttrium-90 (90Y) resin microspheres as a salvage therapy for liver-predominant metastases of colorectal cancer in patients with documented progression after hepatic arterial chemotherapy (HAC) and systemic chemotherapy. Patients and MethodsWe recruited 19 patients who had received a mean of 2.9 prior lines of chemotherapy and ≥ 1 line of HAC. Dose-limiting toxicities (grade 3 or higher) were catalogued using Common Terminology Criteria for Adverse Events version 3.0. At 4 to 8 weeks and 3 to 4 months post SIRT, responses were assessed by carcinoembryonic antigen (CEA), and quantitative imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST). Liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. ResultsMedian follow-up was 31.2 months after SIRT. Within 6 weeks of SIRT, 3 patients (15.8%) experienced grade 3 toxicity. There was no incidence of radiation-induced liver disease. Responses by RECIST, PERCIST, and CEA were, respectively, 0%, 20%, and 32% at 4 to 8 weeks and 5%, 33%, and 21% at 3 to 4 months post SIRT; 53% of patients had stable disease (by RECIST) at 3 to 4 months. Of 19 patients, 4 (21.1%) had liver ablation, 9 (47%) received additional HAC, and 17 (89%) received systemic chemotherapy after SIRT. Median LPFS, PFS, and OS after SIRT were 5.2 months, 2.0 months, and 14.9 months, respectively. ConclusionSIRT was well tolerated and did not prohibit subsequent treatment, resulting in a median OS of 14.9 months in this heavily pretreated population.

Gain of ALK gene copy number to predict lack of response to anti-EGFR treatment in advanced chemorefractory colorectal cancer (CRC) with KRAS/NRAS/BRAF/PI3KCA wild-type status.

3641 Background: KRAS, BRAF, NRAS and exon 20 PIK3CA quadruple wild-type CRC is associated with 41.2% response rate to anti-EGFR treatments. Even in molecular characterized patients, there is still a subset of non responders. The identification of additional predictive biomarkers is an unmet clinical need for treatment personalization. Alterations of ALK oncoprotein may interfere with the biological activity of EGFR through cross-talk of downstream signalling pathways. Methods: This retrospective analysis aimed to investigate the correlation between ALK gene copy number (GCN), assessed by fluorescence in situ hybridization (FISH), and clinical outcome in KRAS/NRAS/BRAF/PI3KCA wild-type chemorefractory advanced CRC patients receiving cetuximab or panitumumab. FISH was perfomed with break-apart ALK (2p23) probes and gain of ALK GCN was defined as a mean of 3 to 5 signals in ≥10% of cells and amplification as ≥6 signals. Association of ALK status with RECIST response was performed by Fisher’s exact test. Results: Forty-one patients were identified, of whom 17 (41%) were ALK GCN positive, whereas the remaining 24 cases (59%) were ALK GCN negative. No ALK translocations were detected. Overall response rate was 19/41 (46%). We observed a partial response in 3/17 patients with ALK GCN positive versus 16/24 patients with ALK GCN negative (18% versus 67%, respectively; P=0.0036). Kaplan-meier curves for comparison of median progression-free and overall survival, as well as correlation with ALK expression by immunohistochemistry, will be presented at the Meeting exploring the whole National Cancer Institute data-set. Conclusions: In this study population with KRAS/NRAS/BRAF/PI3KCA wild-type tumors, the response rate greater than 40% is in line with literature data. ALK GCN may be a biomarker for clinical outcome prediction in advanced chemorefractory CRC patients treated with cetuximab or panitumumab.

Changes in VEGF-A-serum levels after DEBIRI-TACE in patients with liver metastases of chemorefractory colorectal cancer.

93 Background: TACE with irinotecan-loaded drug-eluting beads has shown activity in colorectal liver metastases. Among the factors potentially interfering with its effectiveness is a hypothetical neo-angiogenic reaction due to ischemia. Methods: Patients with predominant liver metastases from CRC which were refractory to chemotherapy and documented tumor progression during or shortly after the last chemotherapy, were prospectively treated with irinotecan-loaded drug-eluting beads with a size of 100-300 µm. Therapy was applied by a temporary catheter placed in the liver arteries. Usually each lobe of the liver was according to the recommended DEBIRI treatment algorithm. Each treatment of one liver lobe was performed with 1 vial of the 100-300 µm DC-Beads loaded with 100 mg irinotecan. Blood samples to measure the VEGF serum levels were taken before TACE and at days 7, 14, and 21 after first treatment. Results: Complete blood samples were taken from 15 patients from 2/11 to 2/12. 60% of patients had an increase of the VEGF-A-Level with a median of 107 %, 40% of patients had a decrease of the VEGF-A-Level with a median of – 39% respectively. The relative decrease of the VEGF-A-Levels depends on a prior liver resection (p=0.05), and a significant decrease was found in patients with a prior bevacizumab therapy (p=0.025). A trend to an increase in VEGF-A-Levels was detected in patients with a low count of liver metastases (p=0.087). Conclusions: These findings show different behavior of the VEGF-A-levels after DEBIRI-TACE, suggesting that the occlusion of blood vessels and subsequent ischemia induces neo-angiogenesis due to these growth factors in a subset of 60% of the patients treated with a DEBIRI-TACE. We found a trend for a lower count of liver metastases, prior liver resection and a prior bevacizumab-therapy, respectively influencing the VEGF-A-Level-changes. The trend toward a decrease in patients with a prior bevacizumab therapy may be due to a neoangiogenesis-pathway other than VEGF-mediated. These first results could implicate that antiangiogenic drugs might be effective as an additive therapy to chemoembolization in a subset of patients, e.g., those with no prior bevacizumab therapy.

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n = 10; or low PTEN, n = 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n = 10; or BRAF mutation, n = 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n = 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n = 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n = 5), and BRAF inhibitor (if BRAF mutation, n = 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit.

Progress in the management of chemorefractory colorectal cancer

Advancements in the management of un-resectable mCRC have been characterised by smallincremental improvements in overall survival whichnow extends beyond 2 years with the addition ofbiological agents to standard fluoropyrimidine-basedchemotherapy regimens. Today, a whole host of newlyidentified targeted therapeutic agents inhibiting one ormore key pathways are being evaluated in phase IIIclinicaltrials(includingafliberceptandregorafenib)

TRICC-c: BIBF 1120 versus placebo in patients receiving oxaliplatin plus fluorouracil and leucovorin (mFOLFOX6) for advanced, chemorefractory metastatic colorectal cancer (mCRC)—A multicenter, randomized phase II trial in progress.

TPS3636 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in western countries. With advances in the treatment of metastatic CRC (mCRC) in the last decade using combination chemotherapy and bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), progression free survival (PFS) in first and second line setting was substantially improved. Tumour angiogenesis is also driven by other factors but VEGF including Platelet Derived Growth Factor (PDGF) and Fibroblast Growth Factor (FGF). BIBF1120 is a potent, orally available triple angiokinase inhibitor that blocks the receptor tyrosine kinase activity of human VEGFR1-3, FGFR1 and -3 and PDGFRα and -β. Thus, BIBF1120 could be an exciting addition to the treatment of patients with chemorefractory CRC. Methods: Randomized, double-blind, placebo-controlled, multicentre, phase II trial of BIBF1120 (orally, 200 mg, bid, d1-d14, Arm A) vs. placebo (Arm B) in patients receiving mFOLFOX6 (oxaliplatin, 85 mg/m2, fluorouracil, 400 mg/m2 bolus and 2400 mg/m2 over 46 h, leucovorin, 200 mg/m2) q14 d for patients (ECOG performance status 0-1) with chemorefractory mCRC who received one prior line of chemotherapy. Scheduled are 90 patients per treatment arm. Primary endpoint: PFS, Secondary endpoints: objective response, overall survival, duration of overall response, safety. Additionally there will be an explorative analysis of predictive biomarkers for BIBF1120. 4 of planned 180 patients have been enrolled. We expect the last patient out in June 2013. (Trial identifier: NCT01362361.)

Molecular profiling of patients (pts) with colorectal cancer (CRC) and matched targeted therapy (MTA) in phase I clinical trials.

3014 Background: Molecular prescreening and biomarker enrichment strategies in Phase 1 trials with targeted therapies are anticipated to improve the outcomes of affected pts. Methods: As part of our personalized oncology program, tumors from pts with advanced chemorefractory CRC were analyzed for specific molecular aberrations (KRAS/ BRAF/ PIK3CA mutations [mut], PTEN and pMET expression) at the Vall d'Hebron Molecular Pathology and Genomics Labs. Those whose tumors were found to have a dysregulation were offered a Phase 1 trial with MTA. Results: During 2010 and 2011, tumor molecular analysis was performed in 254 pts: KRAS mut (80/254, 31.5%), BRAF mut (24/196, 12.2%), PIK3CA mut (15/114, 13.2%), KRAS+PIK3CA mut (9/114, 7.9%), PTEN low (97/183, 53.0% - HSCORE&lt;50; 45/183, 24.6% - PTEN null), KRAS mut + PTEN low (38/138, 20.8%), pMET high (38/64, 59.4% with HSCORE&gt;30). In total, 68 pts (median, age 63 yrs; prior therapies 3), received 82 different matched therapies. Type of MTA: PI3K pathway inh (if PIK3CA mut, n=10; or PTEN low, n=32), MEK+PI3K pathway inh (if KRAS mut, n=10; or BRAF mut, n=1), second-generation anti-EGFR mAbs (if KRAS wild-type, n=11), anti-HGF mAb (if pMET high, n=10), mTOR inh + anti-IGFR-1R mAb (if PTEN low, n=5) and BRAF inh (if BRAF mut, n=3). Median time to treatment failure (TTF) with MTA was 7.9 weeks (CI95%:7.6-8.1) vs. 16.3 weeks (CI95%:13.9-18.7) for their prior systemic antitumor therapy (p&lt;0.001). If prior therapy non-standard (according to NCCN guidelines, n=39), TTF with MTA 7.9 weeks (CI95%:6.8-8.9) vs. TTF with prior therapy 8.7 weeks (CI95%:7.3-10.1). If an approved standard regimen (n=43), TTF with MTA 7.9 weeks (CI95%:7.6-8.1) vs. TTF with prior therapy 21.9 weeks (CI95%:15.0-28.7). Partial response was seen in one pt (1.2%, PI3K inh with PIK3CA mut) and stable disease &gt; 16 weeks in 10 cases (12.2%). Clinical benefit, defined as a TTF ratio ≥ 1.3 (TTF on MTA/ TTF on prior therapy), was seen with 15.9% of the therapies (13/82). Conclusions: Preliminary results suggest that matching chemorefractory CRC patients with targeted agents in early clinical trials based on the current molecular profile does not result in longer TTF compared to their prior therapy.

EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients

BackgroundStandardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined. Materials and methodsWe retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR). ResultsUsing receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% [95% confidence interval (CI)=47.1–70.1) and specificity of 93.3% (95% CI =80.6–100). EGFR FISH-positive patients (N=43, 50.6%) had significantly higher RR (P=0.0001) and significantly longer time to disease progression (P=0.02) than EGFR FISH negative (N=42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy. ConclusionsCRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.

An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy

BackgroundA phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer. Patients and methodsThis open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumumab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated. ResultsOne hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received ≥1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (CI): 8.0–13.4) weeks. Median overall survival time was 6.3 (95% CI: 5.1–6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample. ConclusionsThese findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.