Therapy In mCRC Patients Research Articles

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

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

Long-Term Maintenance Therapy with the TLR-9 Agonist MGN1703 in a Subgroup of Metastatic Colorectal Cancer Patients from the Impact Study

ABSTRACT Background The IMPACT trial assessed the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, as switch maintenance after first line induction therapy in mCRC patients at the dose of 60 mg subcutaneously twice weekly. We report here the updated follow-up of 4 patients who completed the study without disease progression. Methods Patients with mCRC and disease control after induction 1st-line chemotherapy +/- bevacizumab were included in the IMPACT placebo-controlled phase 2 study. The trial was closed after randomization of 59 patients and the final analysis showed a superior effect of MGN1703 compared to placebo: the hazard ratio for the primary endpoint PFS on maintenance was 0.55 (p = 0.041) by local investigator assessment and 0.56 (p = 0.070) by independent radiological review. During the study 3 responses were observed in the MGN1703 arm, two of them appearing as late as 9 months after the start of treatment. Overall 4 patients (the 3 responders to MGN1703 and 1 patient in CR after induction chemotherapy) were still free of progression at time of the study closure and were allowed to continue MGN1703 treatment in compassionate use programs. Results As of April 2014, only 1 patient stopped treatment with MGN1703 due to disease progression after 17 months. Three patients are still not progressing and continue to receive MGN1703 monotherapy in excess of 32, 36, and 40 months. No relevant toxicity or SAE was reported during the extended follow-up and treatment. Patients with normalized CEA and objective response at the end of induction chemotherapy appear to benefit the most from maintenance with MGN1703. Notably, the presence of activated NKT-cells (CD3+/CD56+/CD69+) also appears to predict a benefit, possibly linked to the activation status of the immune system before receiving MGN1703. Conclusions Very prolonged responses with the TLR9 agonists were achieved in a subgroup of mCRC patients, without evidence of relevant toxicity. IMPALA, a large international phase 3 study, aims to confirm the role of MGN1703 as first line switch maintenance in mCRC patients with an objective response to standard induction therapy. Disclosure A. Zurlo: Mologen AG employee and owner of stocks and stock options. All other authors have declared no conflicts of interest.

Optimal duration of systemic treatment in metastatic colorectal cancer.

With the currently available cytotoxic and targeted drugs, metastatic colorectal cancer (mCRC) may be controlled by systemic treatment for a significant period of time. However, many questions remain about the optimal use of drugs and duration of treatment. We reviewed the data from clinical trials on the optimal duration of systemic treatment with chemotherapy and targeted therapy in mCRC patients. The feasibility of chemotherapy-free intervals has been studied in mCRC patients treated with chemotherapy alone, but the results are conflicting. Current data show that oxaliplatin may be safely interrupted, but do not allow a firm conclusion on the safety of a full treatment break of chemotherapy. For targeted therapy, continuous inhibition of intracellular signalling by prolonged administration would theoretically be beneficial for efficacy of treatment, and has been suggested by retrospectively collected data. Recent data from a prospective study show a clinical benefit for maintenance treatment with chemotherapy and bevacizumab with acceptable toxicity and preservation of quality of life. Survival benefits were seen in selected patient subgroups. No data on the optimal duration of treatment with anti-epidermal growth factor receptor agents are currently available. There are no definite data on the safety of chemotherapy-free intervals. Data on targeted therapy support the use of maintenance treatment of chemotherapy plus bevacizumab.

Efficacy and safety of bevacizumab in elderly patients with metastatic colorectal cancer: results from the Czech population-based registry

BackgroundPatients aged 65 years and older represent the majority of patients with metastatic colorectal cancer (mCRC). However, this patient population is often underrepresented in clinical trials and probably undertreated in the clinical practice.MethodsWe have analysed the outcomes of 3,187 mCRC patients treated with first-line bevacizumab based on data from the Czech national registry of mCRC patients aiming to compare the treatment efficacy and safety according to the age categories.ResultsIn total, 2,126 (66.7%), 932 (29.2%), and 129 (4.0%) patients were aged <65 years, 65 to 75 years, and 75+ years, respectively. Median progression-free survival (PFS) was 11.4, 11.3, and 11.8 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.94). Median overall survival (OS) was 26.9, 27.5, and 25.1 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.73). Using multivariable Cox model for both PFS and OS, the patient age was not significantly associated with either PFS or OS. No increase in bevacizumab-related toxicity was observed among the elderly mCRC patients with the exception of hypertension, which was observed in 71 (3.3%), 34 (3.6%), and 10 (7.8%) patients aged <65 years, 65 to 75 years, and 75+ years, respectively.ConclusionsThe results of the present study suggest similar outcome in terms of OS and PFS with bevacizumab-containing therapy in elderly mCRC patients fit for chemotherapy combined with targeted therapy compared to younger patients. Thus, chronological age should not be considered to represent a limitation in prescribing bevacizumab-containing therapy in mCRC patients.

Prognostic value of the Glasgow Prognostic Score in metastatic colorectal cancer in the era of anti-EGFR therapies

The Glasgow Prognostic Score (GPS), combination of C-reactive protein and albumin, has proven its prognostic value in metastatic colorectal cancer (mCRC) patients receiving conventional cytotoxic therapy. More recently, anti-EGFR therapies have been validated in mCRC and roll forward the patients' overall survival (OS). We aimed to evaluate the prognostic accuracy of the GPS in patients receiving anti-EGFR therapy in addition to conventional chemotherapy. From January 2007 to February 2012, consecutive mCRC patients who received 5-fluorouracil-based chemotherapy plus cetuximab were included in the present analysis. Patients were eligible for the study if they met the following criteria: advanced pathologically proven MCRC, age >18 years, adequate renal function (creatinine clearance >40 ml/min), C-reactive protein and albumin and performance status evaluation before treatment initiation. A total of 49 patients received cetuximab plus 5-fluorouracil-based chemotherapy (colon, n = 34; rectum, n = 15) and were treated with a median follow-up of 35 months (16.5-74.7). Median age was 48 years old. In addition to cetuximab, patients received oxaliplatin- (n = 34, 60%) or irinotecan (n = 15, 30%)-based chemotherapy. At time of diagnosis, 55, 29 and 16% of patients had a GPS of 0 (n = 27), 1 (n = 14) and 2 (n = 8), respectively. Fifty-five, 29 and 14 % of patients add one, two or ≥3 metastatic sites, respectively. Considering two groups (GPS = 0 and GPS ≥1), median progression-free survivals were significantly different (p = 0.0084). Median OS in the GPS 0, 1 and 2 groups were 38.2, 14 and 12.1 months, respectively (p = 0.0093). The results of the present study confirm that the GPS is still a simple and effective prognostic factor in the era of cetuximab therapy in mCRC patients.

PCN6 - Systematic Review Of Anti-Vegf Therapies For Metastatic Colorectal Cancer

Anti-angiogenic therapy has become an integral component of treatment for metastatic colorectal cancer patients. During the last 10 years, several studies were conducted to test the safety and efficacy of anti-angiogenic therapies in mCRC patients. This study reviewed the results of randomized controlled trials published in peer-reviewed journals. We searched the MEDLINE, and abstracts from ECCO, ESMO and ASCO until January 2013. Studies were selected for randomized controlled trials on targeted anti-angiogenic drugs in mCRC. Primary endpoints reviewed were progression-free (PFS) and overall survival (OS). Response rates, toxicity and secondary resectability were secondary endpoints. Aggregated data were further analyzed to understand comparative safety and efficacy. Until January 2013, eligible mCRC randomized clinical trials for this review were available for bevacizumab (6 trials including 4523 patients), Cediranib ( 2 trials including 2282 patients), vatalanib (2 trials including 2033 patients) and aflibercept (1 trial including 1226 patients). Overall, anti-angiogenesis therapy for mCRC shows significant OS and PFS benefit versus comparators. The median OS and PFS benefit for regimens containing Bevacizumab were 3 and 3.15 months, versus background chemotherapy. The median OS and PFS benefit for vatalanib containing regimens were statistically insignificant versus background chemotherapy. Anti-angiogenesis therapy with Bevacizumab for mCRC shows significant OS and PFS benefit versus comparators.

The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3′-untranslated region

Although KRAS mutation status has been identified as a strong predictor of response to anti-epidermal growth factor receptor (EGFR) therapies, not all wild-type patients respond. The lethal-7 (let-7) family of microRNAs regulates KRAS activity. A functional polymorphism (rs61764370) has been described in the let-7 complementary site (LCS6). We hypothesized a possible association between this KRAS let-7 LCS6 polymorphism and the response to anti-EGFR treatments in KRAS and BRAF wild-type metastatic colorectal cancer patients (mCRC). We studied the association of the KRAS let-7 LCS6 polymorphism with the response in 100 refractory mCRC patients treated with anti-EGFR antibodies. To assess the real effect of this polymorphism in relation to the treatment administered, we also studied this association in an independent cohort of patients treated exclusively with chemotherapy. The KRAS let-7 LCS6 polymorphism was genotyped using the BioMark system in blood and tumor DNA samples. The BRAF V600E mutation was analyzed in tumor samples. The KRAS let-7 LCS6 G-allele showed a statistically significant association with nonresponse to anti-EGFR-based treatment: 31.9% of patients with the T/T genotype presented a complete or a partial response versus no patients with T/G or G/G genotypes (P=0.004). No statistically significant differences were observed in the patients who received chemotherapy only. These data support the pharmacogenetic role of the KRAS let-7 LCS6 polymorphism in predicting the efficacy of anti-EGFR-based therapy in mCRC patients with the KRAS and the BRAF wild-type genotype.

HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients

Background:In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease.Methods:We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab.Results:Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17⩾2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH−). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH− profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively).Conclusion:HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.

Pharmacoeconomic analysis for K-Ras status–based decisions for first-line therapy of metastatic colorectal cancer (mCRC) in Spain.

438 Background: Personalized medicine is a challenge for current oncology practice. Nowadays there are no pharmacoeconomic analyses in Spain dealing with the clinical and financial impact secondary to K-Ras based decisions for first-line therapy in mCRC patients. So, this study was aimed to assess the cost- effectiveness of K-Ras status based decisions in first- line therapy of mCRC patients in comparison with non- K-Ras based selection of available therapies. Methods: K-Ras mutation prevalence and efficacy of available therapies (measured as response rate and progression free survival) were extracted from randomized clinical trials (RCT) that allowed on-label use of accessible drugs in Spain. Then, we have simulated all possibilities of combination therapies for first-line mCRC based on K-Ras status (wild- type vs mutated) and confronted with all therapies that could be chosen in absence of K-Ras analysis. Prices for all drugs in Spain were used to assume the best- value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by RCT was used to calculate the final budget. 70 kg and 1.7 m were used as reference for patients dose calculations. Results: First-line therapy that includes a biological drug in absence of K-Ras status based decisions implies an incremental cost per 1% of increased response rate of 1,237 euros for irinotecan based doublets and 3,193 euros for oxaliplatin based doublets. On the opposite, K-Ras based decisions reduce costs per objective response by 69% and 35% for irinotecan and oxaliplatin- based schedules in K-Ras wild-type population incorporating cetuximab as biological agent. These data mimic all calculi based on incremental costs secondary to improved progression free survival measured as HR when all scenarios without prior determination of K-Ras status were confronted with K-Ras based decisions. Conclusions: K-Ras based decisions reduces costs per objective response as well as per improved progression free survival. The most cost- effective scenario among all simulated was cetuximab in combination with chemotherapy for patients that harbor wt K-Ras mCRC.

6164 POSTER Vitamin E Supplementation Against Oxaliplatin Induced Peripheral Neuropathy

sites other than colon/rectum after mCRC diagnosis. By anatomic locations, 17.6% of patients had major surgeries on liver or lung (13.4% on liver and 4.9% on lung); and 32.3% had major surgeries on all other anatomic sites. Major surgeries on colon or rectum occurred in 35.9% of patients (32.9% on colon and 4.1% on rectum). Conclusions: Major surgeries are highly prevalent in patients with mCRC from this commercially insured population after mCRC diagnosis. This might have implications for anticancer drug therapy in mCRC patients.

6163 POSTER Electric Stimulation of Anal Sphincter as a Treatment Option for Fecal Incontinence After Ultra-low Coloanal Anastomosis With or Without Intersphincteric Resection

sites other than colon/rectum after mCRC diagnosis. By anatomic locations, 17.6% of patients had major surgeries on liver or lung (13.4% on liver and 4.9% on lung); and 32.3% had major surgeries on all other anatomic sites. Major surgeries on colon or rectum occurred in 35.9% of patients (32.9% on colon and 4.1% on rectum). Conclusions: Major surgeries are highly prevalent in patients with mCRC from this commercially insured population after mCRC diagnosis. This might have implications for anticancer drug therapy in mCRC patients.

Oncosuppressor methylation: A possible key role in colon metastatic progression

K-RAS and BRAF gene mutations are mandatory to set anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients. Due to the relationship of these mutations with tumor epigenotype, we hypothesized the potential role of oncosuppressor methylation of genes involved in K-RAS/BRAF pathway (CDKN2A, RASSF1A, and RARbeta suppressor genes) in inhibiting EGFR signaling cascade. Primary tumor and synchronous liver metastatic tissues of 75 mCRC patients were characterized for promoter methylation by QMSP and for K-RAS and BRAF mutations. RARbeta, RASSF1A, and CDKN2A genes were methylated in 82%, 35%, and 26% of primary tumors, respectively. RASSF1A resulted significantly more frequently methylated in liver metastasis than in primary site (P=0.015), while RARbeta was significantly lower methylated in distant metastasis (P=1.2 × 10(-6)). As regards methylation content, RASSF1A methylation status was significantly higher in liver metastasis with respect to primary tumor (P=0.000) underlying the role of this gene in liver metastatic progression. In our series K-RAS and BRAF were mutated in 39% and 4% of cases, respectively. Methylation frequencies seemed to be unrelated to gene mutations; on the other hand, RASSF1A mean content methylation resulted significantly higher in liver than in primary tumor (288.78 vs. 56.23, respectively, P=0.05) only in K-RAS wild-type cases sustaining a specific role of this gene in metastatic site thus supporting its function in strengthening the apoptotic role of K-RAS. These evidences held the role of oncosuppressor methylation in both colon tumorigenesis and progression and suggested that epigenetic events should be taken into account when biological therapies in mCRC patients have to be set.

Should Oncologists Be Aware in Their Clinical Practice of KRAS Molecular Analysis?

Should Oncologists Be Aware in Their Clinical Practice of <i>KRAS</i> Molecular Analysis?

Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients

BackgroundDespite the consistent clinical results demonstrated by studies on anti-angiogenic drugs targeted against the vascular endothelial growth factor in metastatic colorectal cancer (mCRC) patients, no specific direct/indirect biomarker of their efficacy has been validated. In this field, circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs) have recently been proposed as noninvasive biomarkers. Patients and methodsThe absolute numbers of CEPs, total CECs (tCECs) and their resting (rCECs) and activated subsets were evaluated by multiparameter flow cytometry in 40 mCRC patients at baseline and before the administration of the third and sixth course of a bevacizumab-based first-line treatment. Fifty healthy subjects were utilized as control. ResultsThe overall response rate was 80%, overall clinical benefit was 90% and median progression-free survival (PFS) was 13.8 months. In our patients, tCECs and rCECs were significantly increased compared with healthy subjects. The patients who achieved a radiological response showed, at baseline, a significant decrease of rCECs and a trend in decrease of tCECs in comparison with patients not achieving response. Finally, a baseline absolute number of tCEC and rCEC <40 cells/ml was evidenced in patients with a longer PFS. No correlation was found regarding CEP. ConclusionsOur study suggests significant correlations between both tCEC and rCEC baseline levels and the antitumor efficacy of a bevacizumab-based combination therapy in mCRC patients, thus confirming that these biomarkers could be used in the clinical setting as an early predictor of tumor response.

Association of GRP78 polymorphisms with response and TTP in patients with mCRC treated with FOLFOX/BV or XELOX/BV.

3590 Background: GRP78, a major endoplasmatic chaperone, is suggested to be critical for tumor angiogenesis. Recent data suggested GRP78 protein overexpression as a major player in tumor recurrence and poor survival by protecting cancer cells from apoptosis, promoting metastasis and chemoresistance to doxorubucin hydrochloride in breast tumors. We tested whether germ-line polymorphisms within the GRP78 gene were associated with clinical outcome in mCRC patients treated with FOLFOX/BV or XELOX/BV and investigated if there is a correlation with gene expression levels of VEGF and its receptors. Methods: gDNA was isolated from peripheral blood of 91 patients with mCRC and three potentially functional genotypes (rs391957, rs12009, rs17840761) within the GRP78 gene were determined using PCR-RFLP. mRNA was extracted from laser-capture-microdissected tumor tissue. Intratumoral gene expression levels of VEGF and VEGFR-1,-2 and -3 from 79 patients with mCRC were analyzed by RT-PCR. Results: In univariate analysis two GRP78 SNPs (rs391957 and rs12009) were significantly associated with TTP (Table). In multivariate analysis GRP78rs391957 remained significantly associated with TTP (adjusted p value=0.012). Moreover, two GRP78 polymorphisms (rs391957 and rs12009) were in linkage disequilibrium (D′=0.93 and r2=0.73). Patients harbouring the C-A-T haplotype were at lowest risk to develop tumor progression [HR 0.49 (CI 95 %; 0.29-0.82)] and showed the highest response rate [OR 2.56(CI 95%;1.07- 6.22)]. The three tested GRP78 polymorphisms were not associated with gene expression levels of VEGF or its receptors (p values > 0.05). Conclusions: Our data suggest that polymorphisms in GRP78 gene may be potential predictive markers to FOLFOX/BV or XELOX/BV therapy in mCRC patients. Moreover, GRP78 polymorphisms may play a major role in VEGF-independent tumor angiogenesis. Univariate analysis N Time to progression Median, months (95% CI) P* value GRP78rs391957 0.004 CC 33 7.9 (6.9, 12.4) CT 35 15.8 (10.8, 22.9) TT 5 19.9 (1.9, 38.6) GRP78rs12009 0.021 TT 31 8.1 (7.0, 11.7) TC 36 13.9 (10.8, 22.2) CC 7 19.9 (7.8, 38.6) GRP78rs17840761 0.074 AA 22 8.3 (6.9, 15.0) AG 41 12.4 (8.1, 17.0) GG 13 13.9 (12.4, 38.6) * Log-rank test. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Genentech Response Genetics

Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, irinotecan 240 mg m−2 day 1; q21) or TEGAFOX (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, oxaliplatin 120 mg m−2 day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3–4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1–55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6–51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12–23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies.