Panitumumab In Colorectal Cancer Research Articles

Identifying optimal magnesium replenishment points based on risk of severe hypomagnesemia in colorectal cancer patients treated with cetuximab or panitumumab.

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR). Treatment with cetuximab and panitumumab commonly causes hypomagnesemia, and optimal management of this adverse effect remains unclear. Here, we evaluated the optimal magnesium replacement points based on the risk of severe hypomagnesemia in colorectal cancer patients who received cetuximab or panitumumab. We retrospectively evaluated 184 patients who received cetuximab or panitumumab for colorectal cancer at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019. Univariate analyses were conducted to evaluate the relationship between patient baseline characteristics and development of hypomagnesemia following cetuximab or panitumumab treatment. Variables that were significantly associated with hypomagnesemia in the univariate analyses as well as previously reported risk factors were entered into a multivariate logistic regression model. The incidence of hypomagnesemia was associated with panitumumab treatment, pre-replenishment serum magnesium concentration, treatment duration, and treatment line. Severe hypomagnesemia post-cetuximab or panitumumab treatment was significantly associated with low baseline magnesium concentrations (< 1.8mg/dL; odds ratio 18.100, 95% confidence interval 1.570-210.000; p = 0.020) and low serum magnesium concentrations during treatment (< 1.1mg/dL; odds ratio 93.800, 95% confidence interval 3.510-2510.000; p = 0.007). To minimize the risk of severe hypomagnesemia during anti-EGFR treatment, magnesium replenishment should be initiated in patients with pre-replenishment concentrations of < 1.8mg/dL, preferably before reaching intra-treatment concentrations of < 1.1mg/dL.

Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors.

Cetuximab and panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), and both are widely used in combination with chemotherapy or as monotherapy to treat patients with RAS wild-type metastatic colorectal cancer. Although often considered interchangeable, the two antibodies have different molecular structures and can behave differently in clinically relevant ways. More specifically, as an immunoglobulin (Ig) G1 isotype mAb, cetuximab can elicit immune functions such as antibody-dependent cell-mediated cytotoxicity involving natural killer cells, T-cell recruitment to the tumor, and T-cell priming via dendritic cell maturation. Panitumumab, an IgG2 isotype mAb, does not possess these immune functions. Furthermore, the two antibodies have different binding sites on the EGFR, as evidenced by mutations on the extracellular domain that can confer resistance to one of the two therapeutics or to both. We consider a comparison of the properties of these two antibodies to represent a gap in the literature. We therefore compiled a detailed, evidence-based educational review of the known molecular, clinical, and functional differences between the two antibodies and concluded that they are distinct therapeutic agents that should be considered individually during treatment planning. Available data for one agent can only partly be extrapolated to the other. Looking to the future, the known immune activity of cetuximab may provide a rationale for this antibody as a combination partner with investigational chemotherapy plus immunotherapy regimens for colorectal cancer.

Highlights of This Issue

LHRH receptors are expressed on the cell membrane of prostate cancer cells and may provide novel therapeutic targets in patients with treatment refractory prostate cancer. Liu and colleagues report a phase I trial of AEZS-108, a hybrid molecule that couples an LHRH agonist with doxorubicin. The agent was well tolerated in heavily pretreated patients and showed early signs of efficacy. In addition, the autofluorescent properties of doxorubicin permitted visualization of internalization in circulating tumor cells, highlighting a potential pharmacodynamic predictive marker for future use of this drug.Demcizumab, a humanized antibody targets the Notch pathway component delta-like ligand 4 (DLL4). Notch plays a critical role in the maintenance of tumor cells with stem-cell properties. Smith and colleagues conducted this phase I trial of demcizumab in patients with advanced solid tumors. Downregulation of stem cell-related genes and upregulation of vascular/endothelial genes occurred starting at 2.5 mg/kg every other week. Patients treated at 10 mg/kg every other week had disease stabilization and decreases in tumor size and prolonged exposure resulting in the emergence of delayed cardiac toxicity. Demcizumab shows promising anticancer activity and novel toxicities warranting further investigation.Resistance to the EGFR inhibitors cetuximab or panitumumab in colorectal cancer is caused by the emergence of mutations in the RAS pathway. In biopsies from relapsed patients, however, only a fraction of cells carry RAS mutations, suggesting that wild-type cells can also survive the treatment. Hobor and colleagues report that sensitive cells grow in the presence of cetuximab when in the company of their resistant derivatives. They find that cells bearing acquired RAS mutations over-secrete the EGFR ligands TGFα and amphiregulin, which protect the surrounding wild-type cells. This paracrine network can be targeted to increase the efficacy of anti-EGFR therapies.Genotype-directed therapy using kinase inhibitors is the standard of care for subsets of lung cancer patients whose tumors harbor oncogenic alterations. These alterations are more frequently detected in never smokers with non-small cell lung cancer, but not all patients harbor a known oncogenic alteration. To identify additional targetable alterations, Capelletti and colleagues screened 576 adenocarcinomas from never smokers. They identified FGFR3-TACC3 rearrangements in three patients of this cohort. In vitro experiments demonstrated that this alteration is oncogenic and sensitive to pan-FGFR inhibitors. These findings suggest that patients harboring FGFR3-TACC3 rearrangement should be considered for clinical trials featuring FGFR inhibitors.

Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing

In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4–ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR–ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia.

A feasibility study of a fully automated molecular diagnostic system for mutation analysis of colorectal cancer.

e21074 Background: KRAS and BRAF mutations are strong molecular predictors for efficacy of cetuximab and panitumumab in colorectal cancer (CRC). We have developed a novel, simple, sensitive and fully automated DNA mutation detection system (Toppan Genotyping Analyzer, TGA) based on Invader Plus® technology. Here we report the validation study of our system, comparing it to DS in the detection of KRAS and BRAF mutations. Methods: Assays were set up using plasmids containing major KRAS (G12A, G12C, G12D, G12R, G12S, G12V and G13D) and BRAF (V600E) mutations. Sensitivity and accuracy of the detection method were evaluated with plasmids, as well as cancer cell lines with KRAS or BRAF mutations. DNA samples were extracted from frozen (n=31) and formalin fixed, paraffin embedded (FFPE) samples (n=36). Results: Sensitivity and accuracy assays using genomic DNA derived from cancer cell lines and plasmid DNA showed that the TGA system can detect mutations at a 5% level. The chip-based assay system allows for simultaneous analysis of 23 mutations in one hour (including the PCR process). The system was compared with two sets of DS, which had different primer sites. KRAS mutations detected in both frozen (DS1:12/31, DS2:11/31) and FFPE (DS1:7/36, DS2:8/36) samples were also successfully detected by the TGA. In the samples shown to be wild-type by DS, TGA was able to detect additional mutants in the frozen (vs. DS1:1/31, vs. DS2:2/31) and FFPE (vs. DS1:4/36, vs. DS2:3/36) samples. In addition, the frequency of BRAFmutation in frozen (1/31) and FFPE (0/36) was concordant between DS and TGA. Conclusions: In terms of detection of KRAS and BRAF mutations, TGA is a highly sensitive and accurate system compared to DS. It also possesses several other advantages including its all-in-one chip reaction, simple procedure and excellent reproducibility. The versatility in detecting mutations in DNA samples with different fixative forms makes the TGA a useful system that can be widely applied in both diagnosis and research areas. We hypothesize that TGA is superior to DS for predicting efficacy of molecularly targeted agents, since it has greater sensitivity for detection of mutations associated with drug resistance.

First-Line Panitumumab for Colorectal Cancer

The treatment for patients with advanced colorectal cancer (CRC) has progressed, such that median survival now approaches or exceeds 2 years with

Clinical development of chemotherapy for advanced gastric or colorectal cancer

The treatment of metastatic cancer has developed significantly over the past decade.Median survival time after chemotherapy was reported to be 12 months for gastric cancer. Several clinical trials reported for more than 2 years by introduction of molecular targeting agents, such as bevacizumab, cetuximab and panitumumab for colorectal cancer. In this article we review various treatment options, including cytotoxic and molecular targeted agents, currently available for patients with gastric or colorectal cancer in Japan.

The search for optimal response prediction in cancer leads to a personalized approach

There is a clear need for better response prediction in the management of patients with cancer. Important progress has indeed been made in understanding the underlying mechanisms of tumor growth and targeting important new targets with novel drugs blocking receptors or interfering with one of the important pathways. A long list of new, targeted agents has been developed or is under development. With this comes also the need of new methods and new molecular markers for response prediction. The area of response prediction is booming: functional imaging is becoming a very important tool and aid and the knowledge on molecular markers is growing very rapidly. Functional imaging with positron emission tomography (PET) scan, dynamic contrast-enhanced ultrasonography (DCE-US) and magnetic resonance imaging (MRI) is coming into the research arena and is likely to be implemented in the future in clinical practice. Better validation of the clinical utility of functional imaging techniques is, however, still needed in many clinical situations. A major clinical problem for the use of novel molecular targeted agents is to determine their activity by the use of classic imaging evaluation methods such as computed tomography (CT) and by the use of standard tumor size assessment with Response Evaluation Criteria in Solid Tumors (RECIST). Therefore, functional imaging techniques that could be performed in the evaluation of the early activity and also in the determination of the optimal dose of the new targeted agents are necessary. Dynamic contrast-enhanced (DCE)-MRI and DCE-US, diffusion and perfusion MRI and PET-CT, using new tracers for proliferation, will probably be integrated gradually in the new generation of clinical trials and eventually also in clinical practice. Molecular markers clearly have the potential to help to select cancer patients that are suitable for treatment with a molecular targeted, agent if they are able to predict the activity or the lack of activity of these agents. Among examples of predictive biomarkers for response and clinical activity, there are cKIT mutations for imatinib therapy in gastrointestinal stromal tumors (GIST), epidermal growth factor receptor (EGFR) mutations for erlotinib and gefitinib treatment in nonsmall cell lung cancer (NSCLC), HER-2 gene amplification for the use of trastuzumab in breast cancer, as well as recently HER-2 overexpression in gastric cancer, KRAS mutations as predictors of lack of activity of cetuximab and panitumumab in colorectal cancer and, finally, BRAF mutations for treatment with selective BRAF inhibitors in melanoma. This list is not completed and will certainly be expanded in the near future. Further, some of these biomarkers are not only predictive for response to a given treatment, but they could have also a prognostic role. As an example, BRAF mutations correlate with poor prognosis, lack of cetuximab and panitumumab efficacy and poor response to chemotherapy in metastatic colorectal cancer. The discovery of whole gene signatures, if they would be confirmed predictive and/or prognostic, will for E. Van Cutsem (*) University Hospital Gasthuisberg, Leuven, Belgium e-mail: eric.vancutsem@uz.kuleuven.ac.be

Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal Cancer

Personalized cancer medicine based on the genetic milieu of individual colorectal tumors has long been postulated, but until recently this concept was not supported by clinical evidence. The advent of the epidermal growth factor receptor (EGFR) -targeted monoclonal antibodies cetuximab and panitumumab has paved the way to the individualized treatment of metastatic colorectal cancer (mCRC). Here we discuss the evidence that mCRCs respond differently to EGFR-targeted agents and that the tumor-specific response has a genetic basis. We outline how, from the initial observation that cetuximab or panitumumab as monotherapy is effective only in 10% to 20% of mCRCs, knowledge has being gained on the molecular mechanisms underlying primary resistance to these agents. The role of oncogenic activation of EGFR downstream effectors such as KRAS, BRAF, PIK3CA, and PTEN on response to therapy is discussed. We suggest that CRCs lacking oncogenic alterations in these four genes have the highest probability of response to anti-EGFR therapies and are defined as "quadruple negative." The rapid and effective translation of these findings into predictive biomarkers to couple EGFR-targeted antibodies to the patients who benefit from them is presented as a paradigm of modern clinical oncology. Finally, unresolved questions such as understanding the molecular basis of response as well the mechanisms of secondary resistance are presented as the future fundamental goals in this research field.

Abstract B229: Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer

Abstract Personalized cancer medicine based on the genetic milieu of individual tumors has long been postulated but until recently this concept was not supported by clinical evidence. The advent of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab has revolutionized the therapy of colorectal tumors and paved the way to the individualized treatment of this cancer type. From the initial observation that cetuximab or panitumumab as monotherapy are effective only in 10–20%, of mCRCs, knowledge has being gained on the molecular mechanisms underlying primary resistance to these agents. It has already been unequivocally established that KRAS mutations, which occur in 35–45% of colorectal cancers, preclude responsiveness to EGFR-targeted therapy. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been suggested to give rise to resistance. Molecular profiling of tumor samples and functional analysis of cellular models were preformed to clarify the relative contribution of molecular alterations to resistance. We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥ 2 alterations (p&amp;lt;0.0001). Accordingly, PFS and OS were increasingly worse for patients with tumors harboring none, or ≥ 2 molecular alteration(s) (p&amp;lt;0.001). When expression of PTEN and mutations of KRAS, BRAF and PIK3CA were concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as ‘quadruple negative’, the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. The functional role of mutated KRAS, BRAF and PIK3CA alleles in modulating resistance to cetuximab was evaluated in multiple cellular models in the presence or absence of ligands of the EGF receptor. The introduction of these oncogenic alleles in colorectal cancer cells impaired the therapeutic effect of cetuximab. Accordingly, we propose a molecular mechanism whereby the occurrence of KRAS and BRAF mutations together with the availability of EGF receptor ligands modulate the response to anti EGFR monoclonal antibodies. Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab based therapies. The rapid and effective translation of these findings into predictive biomarkers to couple EGFR-targeted antibodies to the patients that benefit from them represent a paradigm of modern clinical oncology. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B229.

KRAS Mutations and Susceptibility to Cetuximab and Panitumumab in Colorectal Cancer

Recent retrospective evidence from several randomized studies has established that advanced colorectal cancer patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of epidermal growth factor receptor-directed monoclonal antibodies, such as cetuximab or panitumumab. This represents a paradigm-changing event and will have substantial impact on current and future anticancer drug development. These results add to the economic and ethical considerations involved in the development of novel targeted therapies and should increase our scrutiny of mechanisms of resistance and predictive biomarkers while in earlier developmental stages. In this article, we will review the available clinical data and discuss the implications for future drug development in colorectal cancer.

Panitumumab in colorectal cancer

The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.