Cetuximab-based Therapy Research Articles

526PD - Development of a Predictive Score Using Amphiregulin (AREG), Epiregulin (EREG) and Egfr-Fish Expression Levels to Determine Treatment Efficacy in Mcrc Patients Receiving Cetuximab-Based Therapy. Analysis of the German AIO CRC-0104 Trial

526PD - Development of a Predictive Score Using Amphiregulin (AREG), Epiregulin (EREG) and Egfr-Fish Expression Levels to Determine Treatment Efficacy in Mcrc Patients Receiving Cetuximab-Based Therapy. Analysis of the German AIO CRC-0104 Trial

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14–18 months; hazard ratio 0.66, range 0.43–1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.

Concordance and Discordance in Tumor Genomic Profiling

Systematic tumor genomic profiling has the following two overarching objectives in clinical oncology: the matching of a cancer drug to a specific tumor genetic context and the identification of tumors for which use of a specific therapy would prove futile or harmful. The impact of KRAS-oncogene mutations on cetuxumab response in colorectal cancer (CRC) comprises an instructive example of the latter, whereas BRAF and PIK3CA mutations (among many others) are being used to assign patients with cancer to clinical trials of exciting new targeted agents. However, the extent to which genetic heterogeneity modifies both the spectrum of actionable genetic alterations during tumor evolution and their diagnostic evaluation before patient stratification remains a subject of debate. In the article that accompanies this editorial, Vakiani et al present a genomic profiling study of 736 frozen CRC specimens obtained from more than 600 patients. The authors used mass spectrometric genotyping to identify known activating mutations in KRAS, NRAS, BRAF, and PIK3CA oncogenes, which are commonly mutated in CRC. The mutational status of TP53, which is the most common CRC tumor-suppressor gene, was determined by using Sanger sequencing. A subset of tumors was analyzed by using array-based comparative genomic hybridization. The spectrum of genomic aberrations identified was characteristic of CRC. RAS and PIK3CA mutation frequencies (43% and 12%, respectively) were virtually identical in primary and metastatic tumors. BRAF mutations were notably less frequent in metastatic specimens, which may have been related to the aggressive disease course that is typical of this subtype (eg, comparatively few patients with BRAF mutatations may have survived or been candidates for a rebiopsy). TP53 mutation frequencies increased steadily from 8% of adenomas to 53% of metastases. The key findings were derived from the following two subgroups: a set of 84 patients for whom both primary and metastatic specimens were available and a second group of 31 metastatic pairs obtained from the same patient. An initial analysis of these subgroups uncovered the following pivotal observation of the study: the mutational concordance between matched pairs across the five cancer genes analyzed ranged from 89% to 95%. At one level, this result could be interpreted favorably because it provided reassurance against major technical variances in sample preparation or mutation detection. In contrast, a 5% to 10% discordance rate raised two worrisome possibilities that either the genetic testing platforms rendered inaccurate mutation calls in some instance, or patient-matched specimens occasionally harbored distinct mutation profiles. The approach of the authors to sort through the basis for discordant mutational spectra provided a generally instructive framework for clinicians and translational investigators who seek to apply mutational profiling more broadly in the cancer genomic era. Clearly, a 5% to 10% discordance rate between assay results and the ground truth of the lethal tumor fraction could prove highly detrimental to treatment or clinical trials on the basis of genetic criteria. The failure of a diagnostic assay to detect KRAS or NRAS mutations present in CRC tumors (false-negative results) may lead to the futile use of cetuximab (ie, several weeks of ineffective and costly treatment and the potential for unwarranted adverse effects). Conversely, false-positive KRAS results could result in the failure to administer cetuximab-based therapy, which affords clinical benefit in some KRAS wild-type tumors. In other solid tumor contexts (eg, EGFR mutations and erlotinib treatment in non–small-cell lung cancer), mutational false positives might also lead to the erroneous use of anticancer agents. Assortments of methodologic and biologic factors influence the likelihood of false-positive or false-negative tumor genomic profiling results (Fig 1). Certain technical aspects are germane to the genetic assay itself, such as the robustness and reproducibility of the technology used. Another procedural component relates to the quality of the tumor DNA obtained for analysis. In the study by Vakiani et al, fresh or frozen tumor material was used for the primary analysis, which generally yields high-quality tumor genomic DNA. More often, archival specimens stored as formalin-fixed, paraffin-embedded (FFPE) tissue comprise the most accessible clinical option. However, formalin can fragment the genomic DNA and introduce chemical modifications during the fixation and storage process that lead to false-positive mutation calls. The latter effect poses a particular risk when polymerase chain reaction (PCR) followed by Sanger sequencing is applied to small quantities of degraded genomic DNA from FFPE material. Techniques that augment the quantity of genetic material (such as whole-genome amplification) can also produce false-positive mutation calls. Similarly, false-negative results may occur when heavily degraded FFPE DNA is used in small quantities. Known as the allele dropout phenomenon, these mistakes arise when the mutant allele fails to be sampled during PCR amplification. The likelihood of allele dropout JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 24 AUGUST 2

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer

KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.

Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: An analysis of the AIO KRK 0104 trial.

3588 Background: This study investigated the impact of early tumor-shrinkage (ETS) on progression-free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial. ETS was previously shown to be a predictor of treatment response to cetuximab. The present analysis, for the first time, evaluates the correlation of ETS with outcome parameters in patients undergoing capecitabine-based therapy. It also aims to correlate the predictive value of ETS and cetuximab-induced skin toxicity. Methods: The AIO KRK0104 trial was performed as a randomised study comparing capecitabine/oxaliplatin (CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab in the first-line treatment of mCRC. 121 patients were available for evaluation of ETS at 6 weeks. ETS was defined as a relative change of ≥20% in the sum of the longest diameters of target lesions compared to baseline. Results: Tumors of 63 patients (71% KRAS wild-type (wt), 100% skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs. 4.7 months, p<0.001, hazard ratio: 0.37) and OS (31.6 vs. 15.8 months, p=0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in patients with KRAS mutant mCRC. ETS occurred more frequently with CAPOX- vs CAPIRI-based therapy (p=0.05). There was a highly significant correlation between the occurrence of ETS and cetuximab-related skin toxicity of any grade (I-III) (p=0.002). ETS was documented more frequently in patients with liver metastasis (p=0.09), metastatic involvement of <2 organs (p=0.09), KRAS wild-type tumors (p=0.06) and no previous adjuvant chemotherapy (p=0.06). Conclusions: In patients with KRAS wild-type mCRC receiving capecitabine- and cetuximab-based first-line therapy ETS correlates with prolonged PFS and OS. ETS also correlates with cetuximab-induced skin toxicity. Both parameters may therefore serve as post-randomisation surrogate markers of favourable outcome for cetuximab-based treatment.

Year-to-year impact budget analysis of biologic therapies for first-line metastatic colorectal cancer (mCRC) therapy in Spain.

e14144 Background: Pharmacoeconomic studies deal with populations of patients as if they were admitted at the division of medical oncology in the same date. Real patients are treated along the entire year so that budget simulations should be adjusted to chronological patterns of oncological assistance. Deferred budget impact analysis is undergone in order to assess long-run economic implications of clinical decisions on first-line mCRC therapies in Spain. Methods: As metastatic colorectal cancer diagnosis is not affected by seasonal influences, we have created a mathematical model assuming that a single patient is diagnosed every month and this patient has a 53% possibility to harbor a native K-Ras sequence. Calculi were arranged based on median duration of therapy. For bevacizumab-based therapy, budget impact for year t+1 begins at month 5 and beyond. For patients that receive cetuximab-based therapy, budget impact for year t+1 begins at month 7. The same approach was performed for doublets without any monoclonal antibody. Prices for all drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by randomized trials was used to calculate the final budget. 70kg and 1.7 m were used as reference for patient dose calculations. Results: When K-Ras status is not tested and bevacizumab-based schedules are administered to every patient, annual growth of budget increases by 55- 60%. If K-Ras status is analyzed and wild-type patients are treated with cetuximab combinations and mutated patients receive bevacizumab, yearly budget growth amounts to 39-41%. Annual budget growth is minimized (25%) when K-Ras wt patients are treated with cetuximab combinations whereas K-Ras mutated tumours received chemotherapy alone. Conclusions: Duration of therapy plays a key role on budget impact estimations from both overall and year to year perspectives. K-Ras based clinical decisions not only optimize outcomes as measured by response rates but also minimize economic implications on annual budget growths.

Role of c-MET pathway in the outcome prediction of cetuximab-based therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

5520 Background: Activation of the c-MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. In addition, c-MET has been reported in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade resulting a mechanism of acquired resistance to EGFR inhibitors in lung and colorectal carcinoma. We investigated the impact on cetuximab sensitivity of HGF, c-MET, c-MET activation and c-MET gene status in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients. Methods: A single-institution retrospective analysis including 50 HNSCC patients was carried out. For each case, formalin-fixed tumor specimens were assayed for HGF, total and phosphorylated Y1234/35 c-MET (p-c-MET) by immunohistochemistry and c-MET gene by FISH. Overexpression criteria were defined by ROC curves for each protein and amplification was defined by >2 copies in at least two of the three studied tumor areas. Results were analyzed for association with clinico-pathological features and survival outcomes for cetuximab-treated patients (median follow-up 75 months). Results: c-MET overexpression was detected in 26 (52%) of patients, c-MET amplification in 15 (30%) and p-c-MET in 12 (24%). Amplification was associated with c-MET overexpression (p=0.004). HGF overexpression was observed in 8 (12%) associated with c-MET phosphorylation (p=0.001), suggesting a paracrine activation of receptor. No significant association with clinico-pathological parameters was detected. Log-rank test showed significantly worse outcome in c-MET overexpressing patients for progression-free (PFS) (p=0.002) and overall survival (OS) (p=0.045); p-c-MET was correlated with worse PFS (p=0.014) and OS (p<0.001). In multivariate logistic regression analysis, p-c-MET was an independent prognostic factor for PFS (HR 6.5; 95% CI 1.5-8.9). Conclusions: HGF/c-MET pathway correlated with worse outcome in cetuximab-based regimen treated HNSCC patients, acting as a resistance mechanism for EGFR inhibitors and supporting a dual blocking HGF/c-MET and EGFR pathways for treatment of these patients.

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D mutated metastatic colorectal cancer (mCRC)? A meta-analysis of 54 cases.

511 Background: KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified to represent a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question whether first-line treatment of p.G13D mCRCs should contain cetuximab or bevacizumab. Methods: Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic 1st-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. Results: Overall response rate was comparable between cetuximab- and bevacizumab-based regimens (58% vs 57%). Progression-free survival was comparable (8.0 months-cetuximab-group vs 8.7 months bevacizumab-group). Overall survival (OS) was longer in patients treated with cetuximab as first-line therapy (20.1 months vs 14.9 months). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate significantly with poor outcome (p=0.03). Moreover, a strong trend in favour of capecitabine compared to infusional 5-FU (p=0.06) was seen.. Responders among our cohort showed a benefit concerning PFS and OS undergoing cetuximab- but not bevacizumab-based regimen. Conclusions: This retrospective pooled analysis suggests that cetuximab-based first-line therapy in p.G13D mutant mCRC shows similar activity compared to bevacizumab-containing regimen. Infusional 5-FU and oxaliplatin may represent inferior options compared to capecitabine and irinotecan in p.G13D mutant mCRC 1st-line treatment.

Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer

Background:Clinical trials under-represent patients (pts) >65 years. Non-interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs ⩽65 years.Methods:A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and χ2 or Fisher's exact test.Results:A total of 309 and 305 pts aged ⩽65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1–2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P<0.0002) without any difference between age groups (P=0.34). The objective response rates were 37.9% for ages 18–65 years vs 35.4% for >65 years. Progression-free survival (PFS) did not differ between pts 18–65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53–0.87; P=0.0019).Conclusion:This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged ⩽65 and >65 years.

Phosphatase and tensin homolog expression related to cetuximab effects in colorectal cancer patients: A meta-analysis

To investigate the correlation between expression of phosphatase and tensin homolog (PTEN) and cetuximab effects in colorectal cancer. We searched PubMed, EMBASE and ASCO to identify eligible studies. Finally, 8 randomized control studies were included in the meta-analysis. STATA 10.0 Software was used to investigate heterogeneity among individual studies and to summarize all the studies. Risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Compared with 20 of 266 patients with loss of PTEN, 206 of 496 patients with intact PTEN protein expression had a better objective response rate to cetuximab-based therapy (RR, 4.75; 95% CI, 2.59-8.72; P < 0.001). PTEN positivity was associated with better progression-free survival (PFS) (HR, 0.675; 95% CI, 0.473-0.964; P = 0.031) but not with better overall survival (OS) (HR, 0.608; 95% CI, 0.411-0.899; P = 0.013). In patients with KRAS wild-type status, PTEN positivity did not predict a longer PFS or OS (PFS: HR, 0.707; 95% CI, 0.440-1.138; P = 0.154; OS: HR, 0.943; 95% CI, 0.646-1.377; P = 0.761). Expression of PTEN is related to the effect of cetuximab in colorectal cancer patients and should be considered in treatment with cetuximab.

6122 POSTER Impact of Cetuximab-based Therapy and KRas Genotypes in Japanese Patients With Chemotherapy-refractory Metastatic Colorectal Cancer

6122 POSTER Impact of Cetuximab-based Therapy and KRas Genotypes in Japanese Patients With Chemotherapy-refractory Metastatic Colorectal Cancer

Molecular-targeted therapy of head and neck squamous cell carcinoma: beyond cetuximab-based therapy

Cetuximab improves the overall survival of patients with squamous cell carcinoma of the head and neck (SCCHN), in combination either with radiation therapy or with chemotherapy. However, only a minority of patients seem to benefit from cetuximab. This paper will review the different strategies developed either to overcome epidermal growth factor receptor (EGFR) resistance or to inhibit the other relevant activated molecular pathways. Recent trials have investigated the possibility of including anti-EGFR therapies in the multimodal curative treatment of SCCHN in combination with neoadjuvant chemotherapy, concomitant chemoradiation or as maintenance therapy. Second-generation compounds (pan-HER or dual EGFR/HER-2 tyrosine kinase inhibitors) have been designed in an attempt to overcome the postulated resistance to anti-EGFR treatments in SCCHN. Alternative targeted therapies have also been developed to inhibit the other activated molecular pathways. Some of these new treatments have shown either promising activity in preclinical models or interesting preliminary activity in early phase II trials. Phase III trials are now required to validate the findings. Despite an aggressive multimodal approach, more than 50% of patients with SCCHN will relapse. It is therefore essential that targeted agents continue to be evaluated in this disease in the hope of improving outcome.

Spotlight on Cetuximab in Squamous Cell Carcinoma of the Head and Neck†

Cetuximab (Erbitux®) is a chimeric monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). EGFR is overexpressed and/or upregulated in most squamous cell carcinomas of the head and neck (SCCHN); this overexpression is associated with more aggressive disease and poorer prognosis. In the EU, cetuximab is approved in combination with radiation therapy for the treatment of locally advanced SCCHN and in combination with platinum-based chemotherapy for the treatment of recurrent and/or metastatic SCCHN. In randomized, open-label, multinational, phase III clinical trials, cetuximab plus radiotherapy significantly improved the duration of locoregional control (primary endpoint) compared with radiotherapy alone in patients with locally advanced SCCHN, while cetuximab plus first-line platinum-based chemotherapy significantly improved overall survival (primary endpoint) compared with first-line platinum-based chemotherapy alone in patients with recurrent and/or metastatic SCCHN. The efficacy benefits of cetuximab-based combination therapy were achieved without an adverse impact on patients' health-related quality of life. In addition, cetuximab had an acceptable tolerability profile when added to radiotherapy or platinum-based chemotherapy; in particular, it did not exacerbate the toxicities commonly associated with these other treatment modalities. Cetuximab-related adverse events, which include skin rash, hypomagnesemia and infusion-related reactions, are mostly mild to moderate in severity and manageable. Thus, cetuximab-based combination therapy is a valuable treatment option in patients with SCCHN. In the setting of locally advanced, unresectable disease, cetuximab plus radiotherapy offers an alternative approach to the current standard of care, namely platinum-based chemotherapy plus radiotherapy (chemoradiotherapy). Based on informal comparisons, cetuximab plus radiotherapy appears to be at least as effective as chemoradiotherapy and, moreover, less toxic; however, formal comparisons of these regimens are required before their relative efficacy and tolerability can be conclusively determined. In the setting of recurrent and/or metastatic SCCHN, cetuximab plus platinum-based chemotherapy provides a first-line treatment of choice for fit patients in whom palliative chemotherapy is indicated.

Cetuximab-based Therapy is Effective in Chemotherapy-naïve Patients with Advanced and Metastatic Non-small-cell Lung Cancer: A Meta-analysis of Randomized Controlled Trials

Randomized controlled trails (RCTs) where cetuximab added to first-line platinum-based chemotherapy for patients with advanced/metastatic non-small-cell lung cancer (NSCLC) have yielded conflicting results. This meta-analysis intended to evaluate the efficacy and safety of cetuximab-based therapy (CBT) in that setting. We analyzed four eligible RCTs that included 1,003 and 1,015 patients randomized to CBT and control intervention, respectively. As compared with the noncetuximab group, CBT demonstrated an 9% reduction in the risk of disease progression [hazard ratio (HR)=0.91; (CI=0.83-1.00); p=0.06], a 13% reduction in the risk of death [HR=0.87; (CI=0.78-0.96); p=0.005], and an approximately 50% increase in objective response rate [odds ratio (OR)=1.48; (CI=1.22-1.80); p<0.0001]. CBT-related adverse events were similar across comparisons except for toxicities known to be associated with anti-EGFR therapy. CBT produced significant clinical benefit with acceptable toxicity as a first-line strategy in patients with advanced/metastatic NSCLC. Further research is needed to identify markers predictive of cetuximab benefit in that disease.

Impact of KRAS, BRAF, PIK3CA Mutations, PTEN, AREG, EREG Expression and Skin Rash in ≥2nd Line Cetuximab-Based Therapy of Colorectal Cancer Patients

BackgroundTo investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy.MethodsPrimary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.Results KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS.ConclusionsThese results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment.

EGFR Fluorescence In situ Hybridization Pattern of Chromosome 7 Disomy Predicts Resistance to Cetuximab in KRAS Wild-type Metastatic Colorectal Cancer Patients

Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients. We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS). One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients. Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients.

Meta-Analysis of Incidence and Risk of Hypomagnesemia with Cetuximab for Advanced Cancer

Background: Cetuximab is often used in patients with colorectal cancer, head and neck cancer, and other cancers. Hypomagnesemia is a major adverse event that was often ignored in studies. The aim of this meta-analysis is to gain a better understanding of the overall incidence and risk of hypomagnesemia in patients who received cetuximab-based therapy. Methods: Databases, including Pubmed, EMBASE, The Cochrane Library, American Society of Clinical Oncology (2000–2008), and Web of Science, were searched to identify relevant studies. Eligible studies were prospective phase II/III clinical trials of patients with cancer assigned cetuximab at a dose of 400 mg/m² i.v. on day 1 and 250 mg/m² weekly thereafter. The primary endpoint was incidence of hypomagnesemia. Results: Nineteen clinical reports were identified which included a total of 4,559 patients available for analysis, with 3,081 patients assigned cetuximab-based treatment. This result showed a high incidence of grade 3 and 4 hypomagnesemia (5.6%; 95% CI = 3.0–10.2) and a high incidence of all-grade hypomagnesemia associated with cetuximab-based therapy for advanced cancer (36.7%; 95% CI = 22–54.4). Compared with non-cetuximab therapy, cetuximab-based therapy has a higher risk of grade 3 and 4 hypomagnesemia (4.75; 95% CI = 3.661–6.18) and all-grade hypomagnesemia (4.75; 95% CI = 3.661–6.18). Conclusion: Cetuximab-based therapy is associated with a significant risk of hypomagnesemia. Early monitoring and effective management of hypomagnesemia are important for patients that received cetuximab-based therapy.

Cetuximab

Cetuximab (Erbitux®) is a chimeric monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). EGFR is overexpressed and/or upregulated in most squamous cell carcinomas of the head and neck (SCCHN); this overexpression is associated with more aggressive disease and poorer prognosis. In the EU, cetuximab is approved in combination with radiation therapy for the treatment of locally advanced SCCHN and in combination with platinum-based chemotherapy for the treatment of recurrent and/or metastatic SCCHN. In randomized, open-label, multinational, phase III clinical trials, cetuximab plus radiotherapy significantly improved the duration of locoregional control (primary endpoint) compared with radiotherapy alone in patients with locally advanced SCCHN, while cetuximab plus first-line platinum-based chemotherapy significantly improved overall survival (primary endpoint) compared with first-line platinum-based chemotherapy alone in patients with recurrent and/or metastatic SCCHN. The efficacy benefits of cetuximab-based combination therapy were achieved without an adverse impact on patients' health-related quality of life. In addition, cetuximab had an acceptable tolerability profile when added to radiotherapy or platinum-based chemotherapy; in particular, it did not exacerbate the toxicities commonly associated with these other treatment modalities. Cetuximab-related adverse events, which include skin rash, hypomagnesaemia and infusion-related reactions, are mostly mild to moderate in severity and manageable. Thus, cetuximab-based combination therapy is a valuable treatment option in patients with SCCHN. In the setting of locally advanced, unresectable disease, cetuximab plus radiotherapy offers an alternative approach to the current standard of care, namely platinum-based chemotherapy plus radiotherapy (chemoradiotherapy). Based on informal comparisons, cetuximab plus radiotherapy appears to be at least as effective as chemoradiotherapy and, moreover, less toxic; however, formal comparisons of these regimens are required before their relative efficacy and tolerability can be conclusively determined. In the setting of recurrent and/or metastatic SCCHN, cetuximab plus platinum-based chemotherapy provides a first-line treatment of choice for fit patients in whom palliative chemotherapy is indicated.

Cetuximab-based Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: Experience From an Area in Which Betel Nut Chewing Is Popular

This study was undertaken to evaluate the efficacy and safety of cetuximab-based therapy in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) in an area in which betel nut chewing is popular. Twenty-five patients were enrolled in the study from 2004 to 2008, of whom 13 received first-line cetuximab plus chemotherapy and 12 received second-line cetuximab with or without chemotherapy after the failure of cisplatin. In the first-line chemotherapy group, the overall response [complete response (CR) plus partial response (PR)] was 54% and disease control rate [CR + PR + stable disease (SD)] was 62%. In the cisplatin-failure therapy group, the overall response was 16.7% and disease control rate was 50%. Median overall survival (OS) and time to progression (TTP) in the first-line chemotherapy group were 857 days and 147 days, respectively. In the cisplatin-failure therapy group, median OS and TTP were 371 days and 136 days, respectively. The most common grade 3/4 toxicity in both groups of patients was infection/fever (23% in the first-line group, 50% in the cisplatin-failure group), followed by neutropenia (23% in the first-line group, 25% in the cisplatin-failure group). Cetuximab-based therapy is an effective and safe treatment choice for recurrent/metastatic HNSCC in areas where betel nut chewing is popular.

Fc gamma receptor polymorphisms and KRAS status as predictive biomarkers in patients with metastatic colorectal cancer treated with biweekly cetuximab-based salvage therapy.

e13523 Background: Cetuximab has shown a clinically significant antitumor activity against metastatic colorectal cancer (mCRC) both in first and subsequent lines of therapy. Biweekly schedules have shown similar PK/PD behaviour and inhibition of EGFR downstream pathway compared to the weekly schedule. Several molecular factors have been found to predict response to Cetuximab. Among them a role of ADCC has been suggested. We aimed to investigate the association of Fc gamma Receptor (Fcg R) polymorphisms and KRAS mutation with the outcome of mCRC patients (pts) treated with salvage biweekly Cetuximab-based therapy. Methods: Tumor from 66 mCRC pts was screened for KRAS mutations using a sensitive multiplex assay. Fcg RIIa and Fcg RIIIa polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). The results were correlated with objective response (OR), disease control rate (CR+PR+SD>6 months) and progression-free survival (PFS). Results: KRAS mutations were associated with a lower OR (52,9% vs 29%, p=0.04), a lower DCR (68,6% VS 29%, p=0.001) and a shorter PFS (6.6 vs 4.0 months, p=0.0007). Whereas no correlation was found for FCg RII and clinical outcome, pts with V-containing FCg RIII polymorphism had a longer PFS (5.5 vs 3.2 p=0.001) and a significantly higher OR and DCR. The difference in PFS remained significant in both KRAS wild type (wt)(6.7 vs 3.2 months, p=0,036) and mutated pts (4.8 vs 2.6 months, p=0.024), all favouring the V-containing FCg RIII genotype. KRAS mutated pts carrying any V-containing Fcg RIII genotype had a longer PFS than KRAS wt pts with the PP-Fcg RIII allele. Considering KRAS wt and any V-containing FCg RIII genotype as favourable factors, median PFS was 6.7, 4.6 and 2.6 (p=0.002) in pts harbouring 2, 1 or none of them. In the multivariate model, considering clinically relevant parameters, KRAS, Fcg RIII and Köhne index were all significantly associated with PFS. Conclusions: Fcg RIII polymorphisms have a clinically relevant role in cetuximab efficacy, even in KRAS mutated pts. Strategies aimed at enhancing activation of NK cell effector functions in this subset of pts seem warranted. No significant financial relationships to disclose.