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Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS- wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P =.38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P =.02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P =.13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P =.46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758 [ABSTRACT FROM AUTHOR]

Background: The authors sought to forecast survival and enhance treatment decisions for patients with liver metastatic colorectal cancer by using on-treatment radiomics signature to predict tumor sensitiveness to irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) alone (F) or in combination with cetuximab (FC).Methods: We retrospectively analyzed 667 metastatic colorectal cancer patients treated with F or FC. Computed tomography quality was classified as high (HQ) or standard (SD). Four datasets were created using the nomenclature (treatment) - (quality). Patients were randomly assigned (2:1) to training or validation sets: FCHQ: 78:38, FCSD: 124:62, FHQ: 78:51, FSD: 158:78. Four tumor-imaging biomarkers measured quantitative radiomics changes between standard of care computed tomography scans at baseline and 8 weeks. Using machine learning, the performance of the signature to classify tumors as treatment sensitive or treatment insensitive was trained and validated using receiver operating characteristic (ROC) curves. Hazard ratio and Cox regression models evaluated association with overall survival (OS).Results: The signature (area under the ROC curve [95% confidence interval (CI)]) used temporal decrease in tumor spatial heterogeneity plus boundary infiltration to successfully predict sensitivity to antiepidermal growth factor receptor therapy (FCHQ: 0.80 [95% CI = 0.69 to 0.94], FCSD: 0.72 [95% CI = 0.59 to 0.83]) but failed with chemotherapy (FHQ: 0.59 [95% CI = 0.44 to 0.72], FSD: 0.55 [95% CI = 0.43 to 0.66]). In cetuximab-containing sets, radiomics signature outperformed existing biomarkers (KRAS-mutational status, and tumor shrinkage by RECIST 1.1) for detection of treatment sensitivity and was strongly associated with OS (two-sided P < .005).Conclusions: Radiomics response signature can serve as an intermediate surrogate marker of OS. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to guide cetuximab treatment continuation decisions. [ABSTRACT FROM AUTHOR]

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS , NRAS , and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA , PTEN , TP53 , MET , HER3 , IRS2 , FGFR1 , and MAP2K1 , the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To evaluate cost‐effectiveness – from a local perspective – of cetuximab when it is added to conventional chemotherapy for the treatment of metastatic colon cancer. Methods: A Markov model was structured based on the systematic review of the evidence and the opinion of local experts. The economic model consists of three health states: (a) progression free survival (PFS), (b) progressive disease (PD) and (c) death. The basic measure to determine the effectiveness of the intervention was the Quality Adjusted Life Year (QALY); however, other intermediate outcomes of impact on survival were considered, such as 'R0 metastases resections' and 'early tumour shrinkage' (ETS). Quarterly cycles were considered with a time horizon of 19 quarters (approximately 5 years). The analysis perspective was based on the Ministry of Health (MoH). Key findings: The cost per quality adjusted life year (cost/QALY) for chemotherapy + cetuximab treatment (CT/Cet) with respect to the baseline strategy approaches S/. 20 078 (equivalent to 1 Gross Domestic Product per capita [GDP‐pc]). The probabilistic analysis of the ICER (Incremental Cost‐Effectiveness Ratio) shows that, in all the cases, the CT/Cet strategy becomes more cost‐effective with a payment threshold of S/. 30 000 (1.5 GDP‐pc). Likewise, the acceptability curves showed that, from a threshold of S/. 20 000, the intervention with cetuximab becomes more cost‐effective than chemotherapy alone (CT). Conclusions: The cost/QALY was S/. 20 078 (1 local GDP‐pc) for the intervention with CT plus cetuximab. Other results of clinical relevance, such as 'additional R0‐resections', 'additional ETS cases', 'disease progressions avoided' and 'deaths avoided' also favour the combination treatment. [ABSTRACT FROM AUTHOR]

Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment. In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient. This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response. [ABSTRACT FROM AUTHOR]

Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid- capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti- EGFRtherapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as micro-satellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. [ABSTRACT FROM AUTHOR]

Background Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. Methods We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. Results Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. Conclusion Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157) [ABSTRACT FROM AUTHOR]

BACKGROUND: Survival of patients with metastatic colorectal cancer (mCRC) has been significantly improved with the introduction of the monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Novel molecular-targeted agents such as aflibercept and regorafenib have recently been approved. The aim of this review is to summarize and assess the effects of molecular agents in mCRC based on the available phase II and III trials, pooled analyses, and meta-analyses/systematic reviews. METHODS: A systematic literature search was conducted using the meta-database of the German Institute of Medical Documentation and Information. Criteria of the Scottish Intercollegiate Guidelines Network were used to assess the quality of the controlled trials and systematic reviews/meta-analyses. RESULTS: Of the 806 retrieved records, 40 publications were included. For bevacizumab, efficacy in combination with fluoropyrimidine-based chemotherapy in first- and subsequent-line settings has been shown. The benefit of continued VEGF targeting has also been demonstrated with aflibercept and regorafenib. Cetuximab is effective with fluoropyrimidine, leucovorin, and irinotecan (FOLFIRI) in first-line settings and as a single agent in last-line settings. Efficacy for panitumumab has been shown with oxaliplatin with fluoropyrimidine in first-line settings, with FOLFIRI in second-line settings, and as monotherapy in last-line settings. Treatment of anti-EGFR antibodies is restricted to patients with tumors that do not harbor mutations in Kirsten rat sarcoma and in neuroblastoma RAS. CONCLUSION: Among various therapeutic options, the future challenge will be a better selection of the population that will benefit the most from specific anti-VEGF or anti- EGFR treatment and a careful consideration of therapy sequence. [ABSTRACT FROM AUTHOR]

In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [Cl] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% Cl = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS. [ABSTRACT FROM AUTHOR]

Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with anti-tumor effects in the presence of activating KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas from patients who received salvage cetuximab plus irinotecan. The study population was retrospectively identified among metastatic colorectal cancer patients who underwent third-line therapy with cetuximab plus irinotecan in a period when only epidermal growth factor receptor (EGFR) expression was required for anti-EGFR therapy. In 59 patients harboring KRAS mutations, Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS) times. An exploratory subgroup analysis was performed using the rs61764370 (LCS6 T>G) polymorphism that experimentally impairs Let-7 binding to KRAS mRNA. In the whole group, higher Let-7a levels were significantly associated with better survival outcomes. For the primary OS endpoint, the multivariate hazard ratio was 0.82 (95% confidence interval, 0.73--0.91; p=.01). The same findings with an accentuated positive effect of high Let-7a levels on both OS and PFS times were observed in an exploratory analysis of the 45 wild-type LCS6 patients (excluding 14 carriers of the LCS6 G allele variant). All survival associations were confirmed after excluding patients with KRAS codon 13 mutations. Among the clinicopathologic features, high Let-7a levels were associated with grade 2--3 skin toxicity (p = .002). In patients with KRAS mutations, Let-7a analysis may serve to identify subgroups of patients who may still benefit from EGFR inhibition and this may open up new perspectives for alternative treatment strategies. [ABSTRACT FROM AUTHOR]

Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab-capecitabine combination has not previously been tested in elderly patients with advanced CRC. Material and Methods. Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine. Results. The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%-67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%-39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment. Conclusions. Cetuximab plus capecitabine at a dose of 1,000 mg/m2 every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC. [ABSTRACT FROM AUTHOR]

Background Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor. Statins have reported antitumor activity, but it is unknown whether simvastatin can reverse cetuximab resistance in KRAS mutant CRC. Methods Human CRC cell lines with KRAS mutations (LS153, LS174T, DLD1, LoVo, SW403, SW480, SNU175, and LS1034) or with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations (DiFi, SW48, HT29, and RKO) were used to test the effect of cetuximab, simvastatin, and cetuximab plus simvastatin on cell proliferation and apoptosis in vitro. Because BRAFV600E mutant may be responsible for cetuximab resistance in KRAS wild-type cells, we measured the growth of xenograft tumors originating from KRAS mutant and BRAF mutant cells in mice treated with cetuximab alone or plus simvastatin (n = 5 mice per treatment group). We used immunoblot assays to study RAS-regulated activation of BRAF protein after simvastatin treatment. All statistical tests were two-sided. Results Addition of simvastatin (0.2 μM) to cetuximab (0.03–1.0 μM) reduced cell proliferation of KRAS mutant (P < .001) but not of BRAF mutant CRC cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (eg, for tumors originating from DLD1 cells, cetuximab vs cetuximab + simvastatin, mean tumor volume = 49.4 vs 20.2 cm3, mean difference = 29.2 cm3, 95% confidence interval = 19.7 to 38.5, P < .001); treatment with cetuximab alone or in combination with simvastatin had no effect on the growth of BRAF mutant tumors. Conclusion Simvastatin may overcome cetuximab resistance in colon cancer cells with KRAS mutations by modulating BRAF activity and inducing apoptosis. [ABSTRACT FROM PUBLISHER]

Background. Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes. Methods. A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists. Results. Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. Conclusions. Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified. [ABSTRACT FROM AUTHOR]

Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab-naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan-naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA-approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild-type K-RAS tumors. The interpretation of the B-RAF mutation and other molecular markers may further define the appropriateness of anti-EGFR therapy. Recent literature revealed that the first-line use of combined anti-EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve. The Oncologist 2010;15:73-84 [ABSTRACT FROM AUTHOR]

The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%–45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer. [ABSTRACT FROM PUBLISHER]

Background: The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor–targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274). [ABSTRACT FROM PUBLISHER]

The spiraling cost of cancer care, in particular the cost of cancer therapeutics that achieve only marginal benefits, is under increasing scrutiny. Although health-care professionals avoid putting a value on a life, our limited resources require that society address what counts as a benefit, the extent to which cost should factor in deliberations, and who should be involved in these decisions. Professional societies, such as the American Society of Clinical Oncology, government agencies, including the Food and Drug Administration, and insurance companies should be involved. However, no segment of society is better qualified to address these issues than the oncology community. Oncologists must offer clear guidance for the conduct of research, interpretation of results, and prescription of chemotherapies. We review recent drug approvals and clinical trials and comment on their relevance to the issue of the spiraling cost of oncology therapeutics. We suggest some standards that would serve as a starting point for addressing these issues. [ABSTRACT FROM AUTHOR]

The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of colon cancer. This overview of clinical studies describes the effects of administering the targeted agents bevacizumab, cetuximab, and panitumumab, also known as monoclonal antibodies, to treat metastatic colorectal cancer (mCRC) patients. All three targeted agents have been approved for use by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bevacizumab has been shown to extend survival when used in combination with irinotecan and 5-fluorouracil--based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil--based chemotherapy overcomes irinotecan resistance. Cetuximab and panitumumab are both efficacious among refractory mCRC patients with wildtype KRAS tumors. Other targeted agents, for example, the tyrosine kinase inhibitors erlotinib, gefitinib, sunitinib, and vatalanib (PTK787/ZK 222584), are currently in various stages of clinical development. [ABSTRACT FROM AUTHOR]

Purpose. To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods. Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m² i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results. Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1-31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1-25.1 weeks). Conclusion. Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m² i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. [ABSTRACT FROM AUTHOR]

Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC).Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse--human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy-refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitumumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti-EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti-EGFR monotherapy is an effective treatment modality for patients with chemotherapy-refractory advanced CRC. [ABSTRACT FROM AUTHOR]

The authors comment on a study which compared the cost-effectiveness of cetuximab monotherapy in advanced colorectal cancer patients who participated in the National Cancer Institute of Canada trial CO.17. The results indicate that extrapolation of trial-based estimates to the general population requires considering the cost of KRAS mutation testing and would likely lead to even higher incremental cost-effectiveness ratios (ICER) for cetuximab therapy.

The authors comment on a study which describes the role of tumor protein 53 (TP53) as a predictive marker of cetuximab benefit in patients with rectal cancer undergoing neoadjuvant chemoradiation. They examine the biological rationale for suggesting TP53 as a predictive molecular marker of cetuximab effect in rectal cancer. They also discuss the significance of the reported opposite relationship between TP53 status and cetuximab outcomes.