Publications by authors named "Regina Esser"

15 Publications

  • Page 1 of 1

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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June 2021

Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer.

Eur J Cancer 2021 Feb 28;144:291-301. Epub 2020 Dec 28.

Department of Medical Oncology, Internal Medicine 1, General Hospital - Medical University of Vienna, Vienna, Austria.

Aim: This study assessed whether cetuximab 500 mg/m administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m followed by 250 mg/m once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC).

Methods: This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events.

Results: OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715-0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804-1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031-1.617]) and the rates of lung/liver metastases resection (1.419 [1.043-1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858-1.382).

Conclusions: The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC.
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February 2021

Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.

Oncologist 2021 02 14;26(2):e261-e269. Epub 2020 Dec 14.

Tennessee Oncology Sarah Cannon Research Institute, Nashville, Tennessee, USA.

Background: The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.

Materials And Methods: Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.

Results: Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.

Conclusion: PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.

Implications For Practice: Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
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February 2021

Phase II APEC trial: The impact of primary tumor side on outcomes of first-line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild-type metastatic colorectal cancer.

Asia Pac J Clin Oncol 2019 Aug 15;15(4):225-230. Epub 2019 May 15.

National Taiwan University Hospital, Taipei, Taiwan.

Aim: The open-label, nonrandomized, phase II APEC study enrolled 167 patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) to investigate the safety and efficacy of first-line, every-2-weeks cetuximab plus investigator's choice of FOLFIRI or FOLFOX in this patient population.

Methods: A subgroup analysis of the APEC study population by primary tumor location was performed.

Results: A total of 130 patients (81.8%) had left-sided and 29 (18.2%) had right-sided mCRC. Median progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) were 14.0 months, 30.6 months and 68.5% for patients with left-sided tumors and 8.9 months, 24.6 months and 51.7% for patients with right-sided mCRC, concurring with pivotal phase III trial results. In patients with right-sided tumors, median PFS was 15.4 months vs 8.3 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively; median OS was 32.1 months vs 21.8 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively.

Conclusion: The APEC tumor-location subgroup analysis results were largely consistent with available literature regarding the equivalent efficacy of cetuximab plus FOLFIRI/FOLFOX in patients with left-sided RAS wt mCRC. A trend toward improved efficacy with cetuximab plus FOLFIRI compared with cetuximab plus FOLFOX was observed in patients with right-sided tumors; however, a direct comparison between groups cannot be made due to the nonrandomized study design. Nevertheless, the similar ORR observed with either chemotherapy backbone in patients with right-sided RAS wt mCRC suggests a potential role for both regimens in this patient population when cytoreduction is a treatment goal.
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August 2019

Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials.

JAMA Oncol 2017 Feb;3(2):194-201

Department of Hematology and Oncology, University of Munich (Ludwig-Maximilians-Universität), Munich, Germany.

Importance: Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct.

Objective: To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial.

Design, Setting, And Participants: In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon.

Main Outcomes And Measures: Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm.

Results: In the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status.

Conclusions And Relevance: In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments.

Trial Registration: Identifiers: CRYSTAL, NCT00154102, and FIRE-3, NCT00433927.
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February 2017

Awareness, Understanding, and Adoption of Precision Medicine to Deliver Personalized Treatment for Patients With Cancer: A Multinational Survey Comparison of Physicians and Patients.

Oncologist 2016 Mar 17;21(3):292-300. Epub 2016 Feb 17.

Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.

Background: Two separate multinational surveys of oncologists and patients with cancer were conducted to assess the awareness and use of biomarkers in clinical practice. These data explore the self-reported and physician-assessed levels of patient cancer literacy and factors affecting physicians' choice to use biomarkers in treatment decisions.

Patients And Methods: Interviews were conducted via telephone with patients and online with physicians. Physicians had 3-35 years of experience; were treating more than 15 patients/month; and specialized in breast, lung, or colorectal cancer. Patients had received treatment for breast, lung, or colorectal cancer within the previous 5 years.

Results: Interviews with 895 physicians and 811 patients were completed. Most patients and physicians reported that patients understood that a tumor could be tested to determine what treatment would be most effective (78% and 73%, respectively) and that patients would be willing to participate in a personalized treatment plan. Whereas 85% of patients felt that they understood their treatment when it was explained to them, only 23% of doctors felt that their patients were always fully informed. Most physicians (90%) reported using biomarkers; among the 10% not performing biomarker analysis, the most cited obstacles were local availability, speed of obtaining results, and cost.

Conclusion: These data demonstrate wide global use of biomarker testing but with regional variations reflecting cultural and local practice. Self-reported and physician-assessed cancer literacy, although generally high, highlighted important regional variations and the need to provide patients with additional information.
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March 2016

Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial.

Target Oncol 2015 Jun 9;10(2):255-65. Epub 2014 Sep 9.

LungenClinic Grosshansdorf, Woehrendamm 80, 22927, Grosshansdorf, Germany,

The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) investigated the efficacy and safety of weekly and every 2 weeks cetuximab maintenance therapy in this setting. Patients were treated with platinum-based chemotherapy plus cetuximab, and those progression-free after four to six cycles were randomized to every 2 weeks (500 mg/m(2)) or weekly (250 mg/m(2)) cetuximab maintenance. Randomization was stratified for tumor histology and response status. The primary endpoint for a regimen would be reached if the lower boundary of the 95 % confidence interval (CI) for the 1-year survival rate exceeded 55 %. A planned 480 patients were to be randomized. However, enrollment was curtailed following a negative opinion from the European Medicines Agency with regard to the use of cetuximab in this setting. After combination therapy, 311/583 (53.3 %) patients without progression were randomized to maintenance therapy: 157 to every 2 weeks cetuximab and 154 to weekly cetuximab. Baseline characteristics were balanced between these groups and exposure to cetuximab was similar. The 1-year survival rate was 62.8 % (95 % CI, 54.7-70.0) for every 2 weeks cetuximab and 64.4 % (95 % CI, 56.2-71.4) for weekly cetuximab. Safety profiles were similar, manageable, and in line with expectations. Therefore, in patients with advanced NSCLC who were progression-free after four to six cycles of first-line chemotherapy plus cetuximab, weekly and every 2 weeks cetuximab maintenance therapy were associated with similar survival outcomes.
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June 2015

Third ventricular enlargement in early stages of multiple sclerosis is a predictor of motor and neuropsychological deficits: a cross-sectional study.

BMJ Open 2013 Sep 10;3(9):e003582. Epub 2013 Sep 10.

Zentrum für Neurologie und Neurorehabilitation, Luzerner Kantonsspital, Spitalstrasse, Lucerne, Switzerland.

Objectives: Whether transcranal sonography (TCS) depicted third ventricular enlargement as a sign of brain atrophy is predictive for neuropsychological deficits in mildly affected patients with multiple sclerosis (MS).

Design: Cross-sectional study of a cohort of mildly diseased patients with MS.

Setting: Neurological MS outpatient clinic at a large teaching hospital in central Europe.

Participants: Fifty-four patients with MS (16 men, 38 women, mean age 40±10 years, mean disease duration 6±5 years; mean Expanded Disability Status Scale 2±1.3) and 33 healthy controls (12 men, 21 women; 38±11 years) underwent clinical examination, an assessment of the third ventricle width by means of TCS and the Brief Repeatable Battery of Neuropsychological tests for MS, the 25-Feet Foot Walk test, the 9-Hole PEG test, the Beck Depression Inventory and a quantitative fatigue assessment. Statistical analysis was performed with univariate correlation and thereafter by stepwise regression analysis.

Results: Patients' mean third ventricular width (3.9±1.6 mm) was significantly wider compared to controls (3.4±0.8 mm). Using stepwise regression analysis models with age, MS duration, third ventricle width and quantitative fatigue assessment as baseline variables, an increasing third ventricle width significantly correlated with the target variables worsening of motor deficits (p<0.002), worsening of verbal recall (p<0.04) and of visual spatial recall (p<0.005). Severity of depression and of fatigue was unrelated to third ventricular width.

Conclusions: In this cohort of patients with MS with mild disease, third ventricular enlargement was indicative for motor deficits and cognitive impairment, even after considering fatigue as a relevant comorbidity. Third ventricular enlargement by means of TCS seems to be a useful, clinically meaningful parameter to stage patients' disease severity. Follow-up studies must show whether an intraindividual future third ventricular increase indeed signals larger cognitive impairment.
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September 2013

Width of 3. Ventricle: reference values and clinical relevance in a cohort of patients with relapsing remitting multiple sclerosis.

Open Neurol J 2013 3;7:11-6. Epub 2013 May 3.

Department of Neurology, Luzerner Kantonsspital, Spitalstrasse, CH-6000 Luzern, Switzerland ; Department of Internal Medicine, Spital Zollikerberg, Trichtenhauserstr. 20, CH-8125 Zollikerberg, Switzerland.

Objectives: To estimate the quantity of multiple sclerosis (MS) patients with brain atrophy as indicated by third ventricular enlargement using transcranial colourcoded ultrasound (TCCS).

Methods: The width of the 3. ventricle was assessed by TCCS in 70 healthy controls (male 31, female 39, mean age 41 ± 15 years, age range 18 - 79 years), and in a cohort of 54 patients with relapsing remitting MS (male 16, female 38, mean age 40 ± 10 years, median EDSS 2 [1-3]).

Results: In the controls, the width of the 3. ventricle increased with age (without any sex differences) from 3.0 ± 0.76 mm in the age group < 40 years to 4.0 ± 0.74 mm in the age group of 60 years or more (ANOVA p=0.0001). Derived from regression analysis, the upper limit of the 95% Confidence Interval for each year provided cutoff points according to which 14 of 54 patients (25%) exhibited an enlarged 3. ventricle. In a multivariate regression analysis, the width of the 3. ventricle over all MS patients was significantly related to EDSS (Spearman rho , r=0.446, p<0.005) and to MS duration (r=0.319, p<0.005).

Conclusions: Even in MS patients in good clinical conditions the rate of patients with brain atrophy determined by TCCS is high.
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June 2013

Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies.

Eur J Cancer 2013 Apr 19;49(6):1161-8. Epub 2012 Dec 19.

Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients.

Methods: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1-300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical, numbers NCT00122460 and NCT00154102, respectively.

Findings: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit.

Interpretation: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings.
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April 2013

Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study.

World J Gastroenterol 2011 Apr;17(14):1879-88

Department of Hematology-Oncology, National University Hospital, 119074 Singapore, Singapore.

Aim: To evaluate the efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia.

Methods: In this open-label, phase II study, the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially, then 250 mg/m2 every week, with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regimens allowed). The primary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS, and an assessment of the overall response rate (ORR), duration of response, time to treatment failure (TTF), overall survival and the safety profile.

Results: One hundred and twenty nine patients were enrolled from 25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI, 41-59) and median PFS time was 12.1 wk (95% CI: 9.7-17.7). The ORR was 13.8% (95% CI: 8.3-21.2) and disease control rate was 49.6% (95% CI: 40.5-58.8). Median duration of response was 31.1 wk (95% CI: 18.0-42.6) and median overall survival was 9.5 mo (95% CI, 7.5-11.7). The median TTF was 11.7 wk (95% CI: 9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%), neutropenia (8.9%), rash (5.7%) and vomiting (5.7%).

Conclusion: In patients from Asia and Australia, this study confirms the activity and safety of cetuximab plus irinotecan observed in previous studies in Europe and South America.
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April 2011

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study.

Clin Colorectal Cancer 2010 Dec;9(5):282-9

Oncology Center, Hospital SírioLibanês, São Paulo, Brazil.

Background: The aim of this multicenter phase II study was to demonstrate the activity of the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody cetuximab combined with irinotecan in the treatment of Latin American patients with EGFR-expressing metastatic colorectal cancer (mCRC) in whom previous treatment with an irinotecan-containing regimen had failed.

Patients And Methods: Patients received cetuximab, as a 400 mg/m2 initial infusion followed by 250 mg/m2 weekly, plus the same irinotecan regimen that had previously failed, until the occurrence of disease progression or unacceptable toxicity. The primary endpoint was response. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety.

Results: Seventy-nine patients received treatment. One patient had a complete response, 20 had partial responses, and disease was stabilized in 23 patients, giving an overall response rate of 27% and a disease control rate of 56%. The median duration of response was 23.9 weeks. Median PFS was 17.4 weeks, median OS was 9.2 months, and the 12-month OS rate was 38%. The most common adverse events according to System Organ Class were skin and subcutaneous tissue disorders (91% of the patients). Grade 3/4 adverse events occurred in 45 patients (57%), with the most common being diarrhea (20%), neutropenia (11%), and rash (6%). Seven patients (9%) had grade 3/4 acne-like skin rash. No grade 3/4 infusion-related reactions were reported.

Conclusion: Cetuximab in combination with irinotecan is active and tolerable in Latin American patients with mCRC progressing on irinotecan, with a safety profile similar to that described in European studies.
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December 2010

Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial.

World J Gastroenterol 2010 Jul;16(25):3133-43

Institute of Oncology, 1000 Ljubljana, Slovenia.

Aim: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC).

Methods: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117).

Results: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56% vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated.

Conclusion: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
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July 2010

Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication.

Cancer 2010 Apr;116(7):1827-37

Division of Medical Oncology Falck, Niguarda Ca' Granda Hospital, Milan, Italy.

Background: : The multinational MABEL study of 1147 patients with metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen confirmed in a community practice setting the efficacy and safety of cetuximab combined with irinotecan.

Methods: : This report describes a post hoc analysis of the influence of prophylactic premedication on the incidence of infusion-related reactions (IRRs) in the MABEL study. The analysis was focused on the subpopulation of patients premedicated with antihistamines either with (n = 700) or without (n = 422) corticosteroids. Stepwise Cox regression modeling was used to examine the explanatory value of the type of premedication on progression-free survival (PFS) and overall survival (OS) times.

Results: : The incidence of IRRs was lower in the group of patients who received antihistamine plus corticosteroid (9.6%) compared with those who received antihistamine alone (25.6%). A similar trend was seen for grade 3 or 4 IRRs (1.0% vs 4.7%, respectively). The 12-week PFS rates (61% vs 60%), median PFS (16.1 vs 13.1 weeks) and OS (9.2 vs 9.0 months) times for patients who received, respectively, antihistamines with and without corticosteroids were similar. Cox regression modeling did not identify any impact of type of premedication used (antihistamine with or without corticosteroids) on the efficacy of treatment in relation to PFS or OS.

Conclusions: : Prophylactically premedicating mCRC patients with both antihistamine and a corticosteroid appeared to reduce the frequency of cetuximab-associated IRRs. Given that this was a post hoc analysis, caution must be exercised in the interpretation of these data, which require formal confirmation in a randomized study. Cancer 2010. (c) 2010 American Cancer Society.
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April 2010

Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study.

J Clin Oncol 2008 Nov 14;26(33):5335-43. Epub 2008 Oct 14.

Kliniken Essen-Mitte, Essen, Germany.

Purpose: This large, multinational study aimed to confirm in a community practice setting the efficacy and safety of cetuximab plus irinotecan in patients with epidermal growth factor-expressing metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen.

Patients And Methods: The primary objective was to determine the progression-free survival (PFS) rate at 12 weeks. The initial cetuximab dose was 400 mg/m(2) and was followed weekly by 250 mg/m(2); irinotecan (according to prestudy regimen) was given weekly (125 mg/m(2) weekly for 4 of 6 weeks), every 2 weeks (180 mg/m(2) each), or every 3 weeks (350 mg/m(2) each).

Results: The intention-to-treat/safety population comprised 1,147 treated patients who received irinotecan weekly (n = 93); every 2 weeks (n = 670); every 3 weeks (n = 356); or another dose (n = 28). The PFS rate at 12 weeks was 61%, and the median survival was 9.2 months. Treatment was generally well tolerated. The most common treatment-related grades 3 to 4 adverse events were diarrhea (19%), neutropenia (10%), rash (7%), and asthenia (6%). The rate of grades 3 to 4 infusion-related reactions (IRRs; composite adverse event category) was 1% for patients who received both antihistamine and corticosteroid premedication. CONCLUSION Tolerability (except IRR incidence), PFS rate, and overall survival rate were in line with previous results. At 1%, the rate of IRRs in patients who received prophylactic premedication with both antihistamine and corticosteroid is lower than previously reported. MABEL clearly confirms in a community practice setting the efficacy and safety of cetuximab plus irinotecan in the treatment of mCRC.
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November 2008