Cetuximab In First-line Treatment Research Articles

Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort.

Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.

Clinical Observation of mXELIRI and mFOLFIRI Combined with Cetuximab in First-line Treatment of Metastatic Left-side Colon Cancer

Clinical Observation of mXELIRI and mFOLFIRI Combined with Cetuximab in First-line Treatment of Metastatic Left-side Colon Cancer

Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis.

Purpose We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.

Cost-minimization analysis of panitumumab compared with cetuximab for first-line treatment of patients with wild-type RAS metastatic colorectal cancer

Objective:To compare the costs of first-line treatment with panitumumab + FOLFOX in comparison to cetuximab + FOLFIRI among patients with wild-type (WT) RAS metastatic colorectal cancer (mCRC) in the US.Methods:A cost-minimization model was developed assuming similar treatment efficacy between both regimens. The model estimated the costs associated with drug acquisition, treatment administration frequency (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions. Average anti-EGFR doses were calculated from the ASPECCT clinical trial, and average doses of chemotherapy regimens were based on product labels. Using the medical component of the consumer price index, adverse event costs were inflated to 2014 US dollars, and all other costs were reported in 2014 US dollars. The time horizon for the model was based on average first-line progression-free survival of a WT RAS patient, estimated from parametric survival analyses of PRIME clinical trial data.Results:Relative to cetuximab + FOLFIRI in the first-line treatment of WT RAS mCRC, the cost-minimization model demonstrated lower projected drug acquisition, administration, and adverse event costs for patients who received panitumumab + FOLFOX. The overall cost per patient for first-line treatment was $179,219 for panitumumab + FOLFOX vs $202,344 for cetuximab + FOLFIRI, resulting in a per-patient saving of $23,125 (11.4%) in favor of panitumumab + FOLFOX.Conclusions:From a value perspective, the cost-minimization model supports panitumumab + FOLFOX instead of cetuximab + FOLFIRI as the preferred first-line treatment of WT RAS mCRC patients requiring systemic therapy.

PCN152 - Cost-Minimization Analysis of Bevacizumab Verse Cetuximab in First-Line Treatment for Metastatic Colorectal Cancer in Kras Wild-Type Patients in the Supplementary Health Care System in Brazil

PCN152 - Cost-Minimization Analysis of Bevacizumab Verse Cetuximab in First-Line Treatment for Metastatic Colorectal Cancer in Kras Wild-Type Patients in the Supplementary Health Care System in Brazil

A nonrandomized, phase IV trial of FOLFIRI and cetuximab in first-line treatment of metastatic colorectal cancer receiving a predefined skin care and skin prophylaxis aiming to prevent a skin rash.

e20724 Background: Anti-EGFR empowered chemotherapeutic regimens resulted in increased overall survival (OS) and response rates (RR). Anti-EGFR induced skin rash occurs in ~ 70% patients, and ~18% ...

Role of cetuximab in first-line treatment of metastatic colorectal cancer.

The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.

Response Phenotype As a Predictive Biomarker to Guide Treatment With Targeted Therapies

Tumor response is one of the oldest biomarkers in solid tumor oncology, first assessed by manual palpation and simple radiographs, and then in recent decades by computed tomography, magnetic resonance imaging, or more advanced imaging. Clinicians have recognized intuitively that patients with responding tumors do better than those with no response, and those with tumor growth do worse. In this way, clinicians use tumor response to help guide the decision about which patients might benefit from additional treatment despite toxicity, which patients might do better with dose adjustment or delay, and which patients instead require a change in therapy. What magnitude of response is most closely associated with benefit from a specific therapeutic regimen? This is not well understood, in part because of a competing definition of response, termed objective response, which was developed for a very different purpose. Objective response is also an old biomarker, first codified in 1981 to establish a unified system for calculating an objective response rate for a trial. Despite changes in tumor measurement techniques, the definition of objective response has remained mathematically consistent across multiple guidelines, facilitating comparison of modern and historical trial results. But whereas objective response is widely accepted as a tool for trial analysis, it was never intended for clinical use, as clearly stated in the WHO, RECIST version 1.0, and RECIST version 1.1 guidelines. Although objective response per RECIST (defined as a 30% or greater decrease in summed tumor diameters) does have some value as a prognostic marker, some investigators have recently studied whether alternate definitions of response can be derived on the basis of biology rather than historical precedent. These studies aim to identify a specific response phenotype, rather than a tumor genotype, that offers insight into disease biology. Studying patients with advanced colorectal cancer treated with cetuximab, Belgian investigators have shown that a 10% diameter decrease optimally predicts for improved survival in patients with KRAS wild-type cancers. Investigating patients with advanced renal cell carcinoma treated with first-line vascular endothelial growth factor inhibitors, Krajewski et al found that a 10% diameter decrease optimally differentiated patients with a poor prognosis from those with a good prognosis. Studying patients with early-stage esophageal cancer treated with induction chemotherapy, German investigators determined that a 35% reduction in [F]fluorodeoxyglucose uptake on positron emission tomography optimally predicts for improved survival and improved chance of pathologic response. In a study of patients with early-stage non–small-cell lung cancer (NSCLC) treated with a neoadjuvant epidermal growth factor receptor (EGFR) kinase inhibitor, Zhao et al found that 25% volumetric response on computed tomography was best at identifying those cancers harboring EGFR mutations, a population known to have dramatically better outcomes when treated with EGFR kinase inhibitors. In the article that accompanies this editorial, Piessevaux et al add to this literature with a comprehensive biomarker analysis of response magnitude in 1,289 patients with advanced colorectal cancer receiving first-line combination chemotherapy. As their data set, the authors studied tumor measurements from two prospective trials of chemotherapy with or without cetuximab (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer [CRYSTAL] and Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer [OPUS]). These two industry-sponsored trials accrued between 2004 and 2006, and both had imaging submitted centrally for tumor measurements. Given the well-described challenges of measurement variability and their potential impact on the utility of tumor measurements, the use of prospectively acquired measurements is a major strength of this research. Using this rich data set, the authors first identified on multivariate analysis that a greater magnitude of tumor response at 8 weeks was associated with improved progression-free survival (PFS) and overall survival, with hazard ratios (HRs) in the range of 0.749 to 0.923 per 10% diameter decrease. As might be anticipated, and as previously shown for patients enrolled onto phase I studies, magnitude of tumor shrinkage is a prognostic marker. The novelty of the analysis by Piessevaux et al lies in their attempt to use early tumor shrinkage to identify a subset of patients who gain maximal benefit from a targeted therapy (cetuximab) when added to chemotherapy in a randomized trial. This is in contrast to the previously described analyses, all of which studied single-arm trials. Here the authors use a Subpopulation Treatment Effect Pattern Plot analysis, which facilitates comparison of the HR between the two arms across a spectrum of values of a biomarker. Looking first at KRAS-mutant cancers (see Fig 3 of the article by Piessevaux et al), it is clear that the lack of added benefit from cetuximab extends across the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 30 OCTOBER 2

How Do We Optimally use Cetuximab in First-Line Treatment for Metastatic Colorectal Cancer?

A number of Phase II/III clinical trials have now been reported assessing the role of cetuximab use in combination with chemotherapy for the first-line treatment of metastatic colorectal cancer. Here we review the current position of cetuximab in this context from two important perspectives. First, we address whether clinicians should prioritize its use with oxaliplatin- or irinotecan-based chemotherapy doublets. Second, we review the trial evidence for the use of cetuximab in patients suffering from colorectal cancer with wild-type and mutant Ras.

Gemcitabine and oxaliplatin (GEMOX) alone or with cetuximab in first-line treatment of advanced biliary cancers (ABC): Exploratory analyses according to tumor KRAS/BRAF mutations and EGFR expression in a randomized phase II trial (BINGO).

4127 Background: Gemcitabine-platinum regimens are the standard of care for ABC. Whether GEMOX-cetuximab may be beneficial in ABC patients (pts) was tested in BINGO, an international, open-label, randomized phase II study (ASCO 2012). With a 4-month progression-free survival (PFS) rate of 63% [CI: 52-74], the primary endpoint was met (target, ≥60%; GEMOX, 54% [43-65]). However, median PFS (6.1 vs. 5.5 months) and overall survival (OS) (11.0 vs. 12.4 months) were similar in both arms. Available data on KRAS/BRAF mutation rates in ABC pts are sparse. Methods: Planned exploratory endpoints included tumor KRAS/BRAF mutational status (high-resolution melting and DNA sequencing) and EGFR expression score (immunohistochemistry [IHC]), and their impact on patient outcome according to treatment arm. Results: Tumor samples were collected for 91 (61%) consenting pts among the 150 randomized pts, and were suitable for DNA analysis and IHC in 75 (50%) and 77(51%) pts, respectively. Tumor KRAS and BRAF mutations (MT) were found in 14 (19%) and 4 (5%) pts, respectively. High EGFR score (≥ 200) was observed in 18 (23%) pts. 4-month PFS rates did not differ according to tumor KRAS MT (wild-type [WT] vs. MT: 62% vs. 57%, p=0.72), BRAF MT (61% vs. 75%, p=1.00) or EGFR score (≥ vs. <200: 56% vs. 63%, p=0.42) overall, or according to treatment arm (table). PFS and OS (log rank test) also did not significantly differ according to these biomarkers, overall or between treatment arms. Conclusions: Tumor KRAS/BRAF mutations and EGFR overexpression were found in 24% and 23% of pts respectively. With the limit of statistical power in these exploratory analyses, they had no statistically significant prognostic or predictive impact. Clinical trial information: 2007-001200-20. [Table: see text]

DGI-042 Hypomagnesemia as a Possible Marker of Efficacy in Patients with Head and Neck Carcinoma in First-Line Treatment with Cetuximab

BackgroundIt has been reported that the determination of magnesium levels could be used as a surrogate marker of efficacy in chemotherapy regimens with cetuximab.Purpose To investigate the hypomagnesemia caused by...

594P - Canadian Economic Analysis of Bevacizumab, Cetuximab, and Panitumumab in the First Line Treatment of Kras Wild-Type Metastatic Colorectal Cancer (MCRC)

ABSTRACT Background CRC is the second leading cause of cancer death in Canada. Bevacizumab, a recombinant humanised monoclonal antibody that selectively binds to human vascular endothelial growth factor, is approved and funded for first line mCRC use in Canada. A substudy has also confirmed its effectiveness in KRAS wild-type patients. Recent evidence has also shown clinical benefit from anti-epidermal growth factor treatments panitumumab and cetuximab in these patients. Objective: We assessed cost-effectiveness of fluoropyrimidine-based chemotherapy (FBC) alone and in combination with bevacizumab, panitumumab or cetuximab for first line treatment of KRAS wild-type mCRC patients. Methods Cost-effectiveness to the Canadian health care system was estimated using separately reported trial survival and adverse event results for each comparator. We used a Markov model calibrated to progression-free/overall survival, and calculated quality-adjusted life years (QALYs). Health-state resource utilization was derived from published data and Canadian oncologist input. Health state utilities and unit prices were obtained from published literature and standard Canadian sources. Results Results per patient over a lifetime horizon, to a maximum 10 years with 5% discounting are presented below. Comparators are ordered by total cost, and the incremental cost-effectiveness ratio (ICER) of each is determined against the previous non-dominated therapy. Comparator Total Cost Total QALYs Δ Cost Δ QALYs ICER FBC $39,061 1.354 - - - Bevacizumab + FBC $104,054 1.848 $64,993 0.494 $131,631 Panitumumab + FBC $151,776 1.806 $47,722 -0.041 Dominated Cetuximab + FBC $161,596 1.865 $57,542 0.017 $3,327,501 Conclusion For first line treatment of KRAS wild-type mCRC in Canada, bevacizumab + FBC is associated with substantially lower costs than panitumumab + FBC or cetuximab + FBC. All three biologics may be associated with similar QALYs, although; this conclusion was based on the limitation of modelling life expectancy from separate trials. Given these findings, bevacizumab seems likely to offer the best value for money for this patient population. Disclosure D. Lawrence: Donna Lawrence is an employee of OptumInsight under contract with Roche. M. Maschio: Michael Maschio is an employee of OptumInsight under contract with Roche. S. Yunger: Simon Yunger is employee of Roche Canada. N. Aucoin: Dr. Aucoin has participated in advisory boards with Roche and Amgen. M. Weinstein: Dr. Weinstein is a consultant to OptumInsight for research under contract with Roche. All other authors have declared no conflicts of interest.

Cetuximab in first line treatment of metastatic colorectal cancer

The present health technology assessment report evaluates the clinical and economic profile of cetuximab in first-line metastatic colorectal cancer (mCRC) in Italy. The first part of the report addresses the epidemiological, clinical, social and economic impact of mCRC. In the second part, evidence of efficacy, safety and cost-effectiveness of cetuximab and its available alternatives is shown. Finally, a model-based economic evaluation aimed at comparing cetuximab-based re­gimens vs. alternative therapeutic strategies indicated in mCRC in Italy is presented. The model estimates the incremental cost-effectiveness of adding cetuximab to FOLFOX-4 or FOLFIRI based on KRAS status, vs. adding bevacizumab to FOLFOX-4 or vs. FOLFOX-4 or FOLFIRI alone. A theoretical analysis vs. panitumumab has also been performed, despite panitumumab is not yet reimbursed in Italy in first-line mCRC. Survival outcomes, quality of life and costs of patient ma­nagement are estimated through a Markov model, using the Italian National Healthcare Service (NHS) perspective, over a 10 year period, taking into account KRAS status of patients. The results of the pharmaco-economic analysis show that cetuximab + FOLFOX-4 and cetuximab + FOLFIRI are associated with increased survival, increased cost and increased quality adjusted survival, compared to all other treatments currently indicated and reimbursed in Italy. Adding cetuximab to FOLFOX-4 or FOLFIRI, based on KRAS status shows favorable incremental cost-effectiveness ratio (ICER) vs. adding bevacizumab to FOLFIRI or vs. FOLFOX-4 or FOLFIRI alone. ICER of cetuximab (in combination with FOLFOX-4 or FOLFIRI), compared to currently reimbursed alternatives, is estimated between 6 and 13 thousand Euros per QALY gai­ned, depending on alternative treatment. These estimates are robust in extensive sensitivity analyses. As a final result, both clinical and economic evidence analyzed in this health technology assessment leads to recommend cetuximab as preferred option for the first-line treatment of mCRC KRAS wild-type patients in Italy.

Explaining the Unexplainable: EGFR Antibodies in Colorectal Cancer

Cetuximab and panitumumab, monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR), have demonstrated efficacy in the treatment of advanced colorectal cancer as single agents and in combination with conventional chemotherapy. Since the US Food and Drug Administration approval of cetuximab in 2004 and panitumumab in 2006, EGFR mAbs have become standard components of treatment algorithms for this disease. The discovery of KRAS mutations as a negative predictive marker for this class of agents in colorectal cancer has rapidly been integrated into clinical practice and has opened the door for a new era in translational and clinical research. In KRAS wild-type colorectal cancer, EGFR mAbs have documented activity in various therapeutic settings and have been successfully combined with different chemotherapy backbones in randomized trials, including irinotecanand oxaliplatin-based regimens. Until recently, the body of evidence from randomized trials suggested that (1) EGFR mAbs as single agents or in combination with chemotherapy showed activity only in KRAS wild-type colorectal cancer; (2) the observed improvement of progression-free survival (PFS) was independent of the line of therapy in which the EGFR mAb was used; (3) the increased response rate with EGFR mAbs in patients with KRAS wild-type tumors was observed even in trials that did not meet their time-related end points of PFS or overall survival (OS); and (4) cetuximab and panitumumab had interchangeable activity. Several questions remained, however, despite extensive clinical experience with EGFR antibodies. The negative data of the large COIN (Continuous Chemotherapy Plus Cetuximab, or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer) trial, which investigated cetuximab added to an oxaliplatin-based chemotherapy backbone, seemed to contrast with the positive data of the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, which used an irinotecan-based regimen. These findings suggested that there may be a preferred chemotherapy partner for EGFR antibodies. In addition, the randomized phase II trial, OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer), demonstrated that the use of cetuximab in combination with oxaliplatin-based treatment for KRAS-mutated colorectal cancer appeared to have a detrimental effect. Eventually, the well-conducted first-line phase III PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) trial, which investigated the addition of panitumumab to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), appeared to clarify the situation by demonstrating that in KRAS wild-type cancers, an EGFR mAb can indeed add efficacy to a FOLFOX backbone. In addition, PRIME also confirmed that, in KRAS-mutated colorectal cancers, the use of an EGFR mAb added to chemotherapy can decrease efficacy. Although this detrimental effect in KRAS-mutated cancers was initially thought to be linked only to an oxaliplatin-based chemotherapy backbone, recently presented data from the second-line phase III trial PICCOLO (Panitumumab, Irinotecan & Ciclosporin in Colorectal Cancer Therapy; irinotecan with or without panitumumab) demonstrated a similar negative effect on PFS and response rate in this group of patients. In the adjuvant setting, the addition of cetuximab to FOLFOX did not improve outcomes in stage III colon cancer, not even in patients with KRASwild-typetumors. InKRAS-mutatedstageIIIcancers, cetuximab was associated with inferior outcome, mirroring the detrimental effect observed in some trials in the metastatic setting. The most recent National Comprehensive Cancer Network guidelines suggest that cetuximab should be not combined with oxaliplatin. The guidelines, however, somewhat inconsistently do allow the use of panitumumab in combination with FOLFOX, on the basis of results from the PRIME trial. The NORDIC (5-Fluorouracil/Folinate/Oxaliplatin [Eloxatin] [FLOX Regimen] Given Continuously or Intermittently, in Combination With Cetuximab [Erbitux] in First-Line Treatment of Metastatic Colorectal Cancer) trial published in this issue of Journal of Clinical Oncology now adds another layer of confusion to the already complex and somewhat inconsistent results on the use of EGFR mAbs in colorectal cancer. In this first-line phase III study, cetuximab was added to bolus fluorouracil (FU)/leucovorin plus oxaliplatin (FLOX), a combination regimen commonly used in Scandinavia, but not in other parts of the world. The primary end point of the trial was PFS, with secondary end points of OS, response rate, R0-resection rate of metastases, and safety. During the conduct of the trial, KRAS mutation emerged as a negative predictive marker for EGFR mAbs, and a prospective KRAS status–based outcomes analysis was integrated into the trial, but no adjustment of the sample size was performed. In the end, the number of patients in the two main comparison arms, FLOX with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2

Cetuximab in first-line treatment of metastatic colorectal cancer in a real-life setting: Preliminary results of the EREBUS cohort.

621 Background: Cetuximab (CTX) has demonstrated to improve survival outcomes in metastatic colorectal cancer (mCRC), but little data for real-life use is available. Methods: EREBUS is a French multicentre (n=92) hospital-based cohort. Patients initiating CTX in 2009 and 2010 were identified retrospectively from registries of nominative drug dispensations. Those with wild-type KRAS gene receiving 1st-line treatment for mCRC were followed-up for 12 months. Data were collected from patient medical records and response based on physician assessments (CT-Scan). Presented here are preliminary results of the EREBUS cohort about administration regimen and according response rates for patients included in 2009. Results: Of the 190 patients included in the cohort, data has been collected for 160 (84.2%): median age at baseline 65.5 years, 70.6% male. Regarding cancer characteristics, 79.4% of patients had a colon cancer and 53.8% a primary tumor resection. Metastatic sites were liver in 73.1% of patients, peritoneum in 29.4%, lymph nodes in 26.3%, and lung in 25.6%. For patients for which the ECOG status was available (54.4%): 79.3% have an ECOG score between 0 and 1, 20.7% ≥2. Half the patients (48.8%) had only one metastatic site. CTX was given every three weeks to 2 patients (1.3%), every two weeks to 113 of patients (70.6%), and weekly to 45 (28.1%). For those receiving CTX every two weeks: 64.9% had irinotecan-based regimens (vs. 45.5% of those receiving CTX weekly, p=0.03), 31.5% had oxaliplatin-based regimens (vs. 47.7%, p=0.06), median duration of CTX use was 3.8 months (vs. 5.3 months, p=0.69) and that of 1st-line therapy 6.3 months (vs. 7.5 months, p=0.97), 69.0% discontinued 1st-line treatment (vs. 82.2%, p=0.09) – mainly for progression (71.8 vs. 75.7%, p=0.66) or toxicity (20.5 vs. 10.8%, p=0.20). Overall response evaluated for 100 patients receiving CTX every two weeks out of 113 was 46.0% (vs. 52.6%, p=0.49, evaluated for 38 receiving CTX weekly). Conclusions: CTX administration every two weeks was the most frequent regimen. In this preliminary analysis, patients receiving weekly or every two weeks regimens had similar duration of treatment and response rate.

Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study

BackgroundThe randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC). Patients and methodsThe biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented. ResultsOf 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed. ConclusionsThese results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Efficacy and safety of XELIRI plus cetuximab versus XELOX plus cetuximab in first-line treatment of metastatic colorectal cancer (mCRC).

e14122 Background: FOLFIRI, FOLFOX, XELOX and XELIRI in combination with biologics are standard options in mCRC. The primary endpoint was to compare the overall response rate of XELIRI+cetuximab (C...

Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities.

The 2010 American Society of Clinical Oncology Gastrointestinal Cancers Symposium

The epidermal growth factor receptor (EGFR)–targeted antibodies cetuximab, a chimeric monoclonal antibody (MoAb), and panitumumab, a fully humanized MoAb, are approved for metastatic colorectal cancer (mCRC) in the chemotherapy-refractory disease setting. 1 Gallagher DJ Kemeny N Second-line management of metastatic colorectal cancer. Clin Colorectal Cancer. 2008; 7: 25-32 Abstract Full Text PDF PubMed Scopus (5) Google Scholar In the first-line setting, 2 recent large randomized trials evaluated cetuximab combined with either FOLFOX (5-fluorouracil [5-FU]/leucovorin [LV]/oxaliplatin; OPUS; Oxaliplatin and Cetuximab in First-Line Treatment of mCRC) or FOLFIRI (5-FU/LV/irinotecan; CRYSTAL; Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer). Based on the intent-to-treat analyses of these trials, the survival benefit in an unselected patient population was modest with cetuximab plus FOLFIRI and absent with cetuximab plus FOLFOX. 2 Bokemeyer C Bondarenko I Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27: 663-671 Crossref PubMed Scopus (1458) Google Scholar , 3 Van Cutsem E Kohne CH Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360: 1408-1417 Crossref PubMed Scopus (3287) Google Scholar However, based on retrospective analyses of clinical trials that evaluated cetuximab or panitumumab, either as monotherapy or in combination regimens, in patients with mCRC in both the first-line and refractory settings, activating mutations in KRAS, a downstream target of EGFR and other cell receptors, were identified as a predictive biomarker for resistance to EGFR-targeted therapy. 2 Bokemeyer C Bondarenko I Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27: 663-671 Crossref PubMed Scopus (1458) Google Scholar , 3 Van Cutsem E Kohne CH Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360: 1408-1417 Crossref PubMed Scopus (3287) Google Scholar , 4 Amado RG Wolf M Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26: 1626-1634 Crossref PubMed Scopus (2775) Google Scholar , 5 Chu E Clinical colorectal cancer: “2008 - the year in review.”. Clin Colorectal Cancer. 2009; 8: 9-10 Abstract Full Text PDF PubMed Scopus (3) Google Scholar In these analyses, the addition of EGFR-targeted antibodies did not enhance progression-free survival (PFS) in patients whose tumors expressed mutant KRAS but significantly improved PFS in patients with wild-type KRAS tumors. Importantly, however, it should be noted that not all patients whose tumors express wild-type KRAS derive clinical benefit. In fact, up to 70%-80% of patients with wild-type KRAS will be resistant to anti-EGFR therapy. Thus, additional biomarkers involved in EGFR signaling such as B-Raf, which is downstream of KRAS, are being investigated. 6 Walther A Johnstone E Swanton C et al. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009; 9: 489-499 Crossref PubMed Scopus (539) Google Scholar Recently, updated efficacy and biomarker analysis results from 2 phase III trials evaluating panitumumab or cetuximab in the first-line treatment of patients with metastatic KRAS wild-type colorectal tumors were presented at the American Society of Clinical Oncology (ASCO) 2010 Gastrointestinal Cancers Symposium held January 22-24, 2010, in Orlando, FL. 7 Siena S, Cassidy J, Tabernero J, et al. Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): PRIME trial. Presented at: the 2010 ASCO Gastrointestinal Cancers Symposium; January 22-24, 2010; Orlando, FL. Abstract 283. Google Scholar , 8 Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): The influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial. Presented at: the 2010 ASCO Gastrointestinal Cancers Symposium; January 22-24, 2010; Orlando, FL. Abstract 281. Google Scholar

First-line targeted therapies in the treatment of metastatic colorectal cancer – role of cetuximab

Worldwide, colorectal cancer (CRC) is the fourth most commonly diagnosed malignant disease and the second leading cause of cancer-related death in Western nations. In 2008 there were an estimated 148,810 new cases and 49,960 deaths in the US. For several years different chemotherapeutic regimens, based on fluoropyrimidines, irinotecan and oxaliplatin, have been used in advanced CRC, but survival is still unsatisfactory. New targeted therapies, including drugs and monoclonal antibodies (MoABs), show great promise in the fight against CRC and have shown activity in different disease settings. Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer (mCRC). As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The combination of this drug with classical chemotherapies has shown better clinical profiles reflected in an improvement in overall and progression-free survival. Clinical trials established the role of cetuximab, particularly with irinotecan, in irinotecan-refractory/heavily pretreated patients. Whereas cetuximab has a clear indication in the salvage setting, its role in first-line therapy remains investigational. It is particularly encouraging that cetuximab may enhance curative opportunities in patients with early metastatic disease, suggesting that adding cetuximab in first-line therapy may downstage disease in some patients, and, as a result, allow potentially curative resection of previously unresectable metastases. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit, and the role of cetuximab in first-line treatment of metastatic CRC.