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Panitumumab (Vectibix)

Web Resources: Panitumumab (Vectibix)
Latest Research Publications

Web Resources: Panitumumab (Vectibix) (6 links)


Latest Research Publications

Al-Hajeili M, Marshall JL, Smaglo BG
Neoadjuvant Treatment for Surgically Resectable Metastatic Colorectal Cancer.
Oncology (Williston Park). 2016; 30(1):10-6 [PubMed] Related Publications
The curative surgical resection of metastatic disease in patients with stage IV colorectal cancer with a limited tumor burden is standard of care. However, the role for neoadjuvant medical therapy and the ideal composition of that therapy are not established. Several neoadjuvant medical therapies, including standard advanced colorectal cancer chemotherapy regimens-such as folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); folinic acid, 5-FU, and irinotecan (FOLFIRI); and folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI)-have been evaluated, as has the addition of the biologic agents bevacizumab, panitumumab, and cetuximab. Those patients who are immediate surgical candidates do not seem to benefit from a neoadjuvant medical approach and should proceed directly to surgical resection. Those patients who are not surgical candidates at presentation can in some instances achieve a conversion of disease to a curable state with systemic therapy. Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.

Lo L, Patel D, Townsend AR, Price TJ
Pharmacokinetic and pharmacodynamic evaluation of panitumumab in the treatment of colorectal cancer.
Expert Opin Drug Metab Toxicol. 2015; 11(12):1907-24 [PubMed] Related Publications
INTRODUCTION: Integration of targeted therapy and additional chemotherapy options has improved median overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC). Cetuximab and panitumumab are examples of targeted therapies, specifically against the epidermal growth factor receptor (EGFR). This review focuses on Panitumumab, a fully human IgG2 monoclonal antibody, which inhibits key oncogenic downstream cell signalling pathways. Panitumumab and cetuximab have improved tumour response rate, progression-free survival, and OS in mCRC patients in whom the RAS (Rat Sarcoma) gene is of Wild Type (WT) status.
AREAS COVERED: The EGFR signalling pathway and preclinical, Phase I and Phase II clinical studies on the pharmacokinetic, pharmacodynamic and safety evaluation of panitumumab are presented. Phase III studies utilising panitumumab in the first, second and third line setting in mCRC are also described.
EXPERT OPINION: Panitumumab exhibits excellent pharmacokinetics and pharmacodynamics by way of uncomplicated dosing, non-existent drug interactions, minimal infusion reactions and manageable side effects, making it a suitable target for combination treatments. However, innate and acquired resistances are still obstacles. To overcome this, experimented strategies are ongoing, particularly in patients with Her-2 and BRAF gene alterations. Novel biomarkers to improve patient selection and second-generation targeted antibodies are in development.

Henricks LM, Schellens JH, Huitema AD, Beijnen JH
The use of combinations of monoclonal antibodies in clinical oncology.
Cancer Treat Rev. 2015; 41(10):859-67 [PubMed] Related Publications
Treatment with monoclonal antibodies is becoming increasingly important in clinical oncology. These antibodies specifically inhibit signaling pathways in tumor growth and/or induce immunological responses against tumor cells. By combining monoclonal antibodies several pathways may be targeted simultaneously, potentially leading to additive or synergistic effects. Theoretically, antibodies are very suitable for use in combination therapy, because of limited overlapping toxicity and lack of pharmacokinetic interactions. In this article an overview is given of preclinical and clinical data on twenty-five different combinations of antibodies in oncology. Some of these combinations have proven clinical benefit, for example the combination of trastuzumab and pertuzumab in HER2-positive breast cancer, which exemplifies an additive or synergistic effect on antitumor activity in clinical studies and the combination of nivolumab and ipilimumab, which results in significant increases in progression-free and overall survival in patients with advanced melanoma. However, other combinations may lead to unfavorable results, such as bevacizumab with cetuximab or panitumumab in advanced colorectal cancer. These combinations result in shorter progression-free survival and increased toxicity compared to therapy with a single antibody. In summary, the different published studies showed widely varying results, depending on the combination of antibodies, indication and patient population. More preclinical and clinical studies are necessary to unravel the mechanisms behind synergistic or antagonistic effects of combining monoclonal antibodies. Most research on combination therapies is still in an early stage, but it is expected that for several tumor types the use of combination therapy of antibodies will become standard of care in the near future.

Leone F, Marino D, Cereda S, et al.
Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study).
Cancer. 2016; 122(4):574-81 [PubMed] Related Publications
BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.
METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m(2) ) and oxaliplatin (100 mg/m(2) ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion.
RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A.
CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC.

Yamada M, Iihara H, Fujii H, et al.
Prophylactic Effect of Oral Minocycline in Combination with Topical Steroid and Skin Care Against Panitumumab-induced Acneiform Rash in Metastatic Colorectal Cancer Patients.
Anticancer Res. 2015; 35(11):6175-81 [PubMed] Related Publications
BACKGROUND: Although the anti-EGFR monoclonal antibody panitumumab is effective in treating colorectal cancer, the occurrence of severe skin disorders often discontinues therapy. Herein, we investigated by a retrospective chart review the effect of prophylactic oral minocycline in combination with skin treatment using moisturizer on the incidence of skin disorders and tumor response in metastatic colorectal cancer patients who received panitumumab.
PATIENTS AND METHODS: In a total of 55 patients, 38 patients were eligible, consisting the pre-emptive group (N=25) and reactive group (N=13). Acneiform rash and other adverse events were graded according to the CTCAE v4.0.
RESULTS: The occurrence of acneiform rash (grade ≥2) was significantly lower in pre-emptive group than in reactive group (44.0% vs. 84.6%, p=0.04). No significant differences in the occurrence of other adverse events were observed between the two groups. Tumor response was not significantly different between the two groups (36.0% vs. 7.7%, OR, 6.75; 95% confidence interval (CI)=0.75-60.76, p=0.12). Mean time to treatment failure was 149.7 days and 110.2 days in the pre-emptive group and reactive treatment group, respectively (HR=0.58; 95% CI= 0.26-1.28, p=0.18).
CONCLUSION: Prophylactic oral minocycline combined with skin care reduced panitumumab-induced acneiform rash without a significant influence on tumor response.

Trojan J, Mineur L, Tomášek J, et al.
Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review.
PLoS One. 2015; 10(10):e0140717 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported.
METHODS: The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey.
RESULTS: In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme.
CONCLUSIONS: There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.

Liu X, George GC, Tsimberidou AM, et al.
Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.
BMC Cancer. 2015; 15:713 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.
METHODS: Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.
RESULTS: Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).
CONCLUSION: Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.

Bertotti A, Papp E, Jones S, et al.
The genomic landscape of response to EGFR blockade in colorectal cancer.
Nature. 2015; 526(7572):263-7 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

Misale S, Bozic I, Tong J, et al.
Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.
Nat Commun. 2015; 6:8305 [PubMed] Free Access to Full Article Related Publications
Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

Khelwatty SA, Essapen S, Seddon AM, et al.
Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers.
Br J Cancer. 2015; 113(7):1010-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The human epidermal growth factor receptor (EGFR) is an important target for cancer treatment. Currently, only the EGFR antibodies cetuximab and panitumumab are approved for the treatment of patients with colorectal cancer. However, a major clinical challenge is a short-term response owing to development of acquired resistance during the course of the treatment.
METHODS: In this study, we investigated the molecular mechanisms underlying development of acquired resistance in DiFi colorectal cancer cells to the anti-EGFR mAb ICR62 (termed DiFi62) and to the small molecule tyrosine kinase inhibitor (TKI) gefitinib (termed DiFiG) using a range of techniques.
RESULTS: Compared with the findings from parental DiFi and DiFiG cells, development of acquired resistance to anti-EGFR mAb ICR62 in DiFi62 cells was accompanied by an increase in cell surface EGFR and increased phosphorylation of HER-2 and HER-3. Interestingly, DiFi62 cells also acquired resistance to treatment with anti-EGFR mAbs cetuximab and ICR61, which bind to other distinct epitopes on the extracellular domain of EGFR, but these cells remained equally sensitive as the parental cells to treatment with pan-HER inhibitors such as afatinib.
CONCLUSIONS: Our results provide a novel mechanistic insight into the development of acquired resistance to EGFR antibody-based therapy in colorectal cancer cells and justify further investigations on the therapeutic benefits of pan-HER family inhibitors in the treatment of colorectal cancer patients once acquired resistance to EGFR antibody-based therapy is developed.

Liang RF, Zheng LL
The efficacy and safety of panitumumab in the treatment of patients with metastatic colorectal cancer: a meta-analysis from five randomized controlled trials.
Drug Des Devel Ther. 2015; 9:4471-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The efficacy of adding panitumumab to chemotherapy remains controversial in the treatment of metastatic colorectal cancer (mCRC). Thus, we conducted this meta-analysis to assess the efficacy and safety of this combination regimen in patients with mCRC.
METHODS: The PubMed, Embase, and Web of Science databases were comprehensively searched. Eligible studies included randomized controlled trials (RCTs) that estimated the efficacy of panitumumab with or without chemotherapy in the treatment of patients with mCRC. Hazard ratio (HR), risk ratio (RR), and 95% confidence intervals (CIs) were calculated, and heterogeneity was tested using I (2) statistics.
RESULTS: Four studies involving a total of 3,066 patients were included in this meta-analysis. The addition of panitumumab to chemotherapy significantly improved progression-free survival (PFS) (HR =0.84, 95% CI =0.78-0.91, P=0.000) and the objective response rate (ORR) (RR =2.18, 95% CI =1.13-4.22, P=0.021) compared to chemotherapy alone, but no effect was noted on overall survival (OS) (HR =0.97, 95% CI =0.89-1.05, P=0.402). Subgroup analysis based on KRAS gene status revealed that the combined therapy significantly improved PFS (HR =0.71, 95% CI =0.57-0.88, P=0.002) and ORR (RR =2.43, 95% CI =1.21-4.90, P=0.013) in patients with wild-type KRAS tumors. Irinotecan-based chemotherapy plus panitumumab significantly prolonged PFS in patients with mCRC (HR =0.84, 95% CI =0.76-0.94, P=0.002). The combined treatment also increased the incidence of grade 3/4 adverse events.
CONCLUSION: This meta-analysis indicates that the combination of panitumumab and chemotherapy effectively improved PFS and ORR, but it did not prolong OS. However, as the number of studies in the meta-analysis was limited, more large-scale, better-designed RCTs are needed to assess the combination of panitumumab and chemotherapy.

Whittle JR, Lickliter JD, Gan HK, et al.
First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma.
J Clin Neurosci. 2015; 22(12):1889-94 [PubMed] Related Publications
There are limited treatment options for patients with recurrent glioblastoma (GBM). The EnGeneIC delivery vehicle (EDV) is a novel nanocellular (minicell) compound which packages theoretically effective concentrations of chemotherapeutic drugs that are designed to target tumors via minicell-surface attached bispecific proteins (EnGeneIC, Lane Cove West, NSW, Australia). Epidermal growth factor receptor (EGFR) is overexpressed in 40-50% of patients with GBM and is a promising target for new therapeutics. (V)EDVDox contains doxorubicin (Dox) within the minicells and targets EGFR through Vectibix (V; Amgen Biologicals, Thousand Oaks, CA, USA). We conducted a first in human Phase I study of (V)EDVDox in adults with recurrent GBM expressing EGFR on immunohistochemistry, following standard therapy including radiation and temozolomide, to establish a safe maximum tolerated dose and determine a recommended Phase II dose (RPTD). (V)EDVDox was administered weekly in an 8week cycle, with dose escalation in successive cohorts of patients using a standard 3+3 design. In total, 14 patients were treated at three dose levels, and the RPTD was identified as 5×10(9)(V)EDVDox. Overall (V)EDVDox was well tolerated, with no dose limiting toxicity and no withdrawals from the study due to adverse events. The most common adverse events were nausea, fever, and chills or rigors, experienced in seven, five and five patients, respectively. Transient uncomplicated hypophosphatemia was seen in seven patients and was not dose-related. Our results demonstrate that (V)EDVDox, up to a dose of 5×10(9)(V)EDVDox weekly, is well tolerated in patients with recurrent GBM.

Chan DL, Pavlakis N, Shapiro J, et al.
Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature.
PLoS One. 2015; 10(8):e0135599 [PubMed] Free Access to Full Article Related Publications
IMPORTANCE: The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.
OBJECTIVE: To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC.
DATA SOURCES: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.
STUDY SELECTION: Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations.
DATA EXTRACTION AND SYNTHESIS: Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity.
RESULTS: EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002).
CONCLUSION AND RELEVANCE: The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.

Modest DP, Stintzing S, von Weikersthal LF, et al.
Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer.
J Clin Oncol. 2015; 33(32):3718-26 [PubMed] Related Publications
PURPOSE: We investigated choice and efficacy of subsequent treatment, with special focus on second-line therapy, in the FIRE-3 trial (FOLFIRI plus cetuximab [arm A] or bevacizumab [arm B]) for patients with KRAS wild-type metastatic colorectal cancer.
PATIENTS AND METHODS: Start of subsequent-line (second or third) therapy was defined as use of an antitumor drug that was not part of the previous regimen. We evaluated choice, duration, and efficacy of subsequent therapy and determined the impact of subsequent-line treatment on outcome of patients in FIRE-3.
RESULTS: Of 592 patients in the intent-to-treat population, 414 (69.9%) received second-line and 256 (43.2%) received third-line therapy. In subsequent treatment lines, 47.1% of patients originally assigned to arm A received bevacizumab, and 52.2% originally assigned to arm B received either cetuximab or panitumumab. Oxaliplatin was subsequently used in 55.9% (arm A) and 53.2% (arm B) of patients. Second-line therapy was administered for a median duration of 5.0 versus 3.2 months (P < .001) in study arm A versus B. Progression-free (6.5 v 4.7 months; hazard ratio, 0.68; 95% CI, 0.54 to 0.85; P < .001) and overall survival (16.3 v 13.2 months; hazard ratio, 0.70; 95% CI, 0.55 to 0.88; P = .0021) from start of second-line therapy were longer in patients in arm A compared with arm B.
CONCLUSION: Our data suggest that the sequence of drug application might be more important than exposure to single agents. In patients with RAS wild-type tumors, first-line application of anti-epidermal growth factor receptor-directed therapy may represent a favorable condition for promoting effective subsequent therapy including antiangiogenic agents.

Del Prete M, Giampieri R, Faloppi L, et al.
Panitumumab for the treatment of metastatic colorectal cancer: a review.
Immunotherapy. 2015; 7(7):721-38 [PubMed] Related Publications
In recent years, the treatment of metastatic colorectal cancer (mCRC) has evolved significantly with the increase of new therapeutic options, leading to an improved median survival for these patients. In particular, the identification of molecular targets in tumor cells has led to the introduction of biological drugs for the treatment of mCRC. Panitumumab is a fully human monoclonal antibody that binds the EGF receptor of tumor cells and inhibits downstream cell signaling with antitumor effect on inhibition of tumor growth. Its use has been approved by randomized clinical trials as monotherapy in chemorefractory patients or combined with chemotherapy in the treatment of RAS wild-type mCRC, where it demonstrated a significant improvement in survival and response rate. The purpose of this review is to analyze the use and efficacy profile of panitumumab, particularly focusing on recently reported data on its use, and future perspectives in patients with mCRC.

Kavuri SM, Jain N, Galimi F, et al.
HER2 activating mutations are targets for colorectal cancer treatment.
Cancer Discov. 2015; 5(8):832-41 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.
SIGNIFICANCE: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer.

Hecht JR, Douillard JY, Schwartzberg L, et al.
Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer.
Cancer Treat Rev. 2015; 41(8):653-9 [PubMed] Related Publications
RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations—including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4—can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.

Piton N, Lonchamp E, Nowak F, et al.
Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping.
Cancer Epidemiol Biomarkers Prev. 2015; 24(9):1416-8 [PubMed] Related Publications
In metastatic colorectal cancer, KRAS and NRAS genotyping is mandatory before prescription of panitumumab or cetuximab. In order to perform such molecular tests, the French National Cancer Institute has set up a nationwide network of molecular centers. We report here the percentage of these mutations according to a prospective nonselected cohort of incident metastatic colorectal carcinoma patients. A total of 6,803 patients were tested between July 1, 2013, and December 31, 2013. Overall, 49.06% of patients harbored a mutation in either KRAS or NRAS. Mutations of NRAS exons 3 and 4 were very rare. No NRAS exon 3 at c.59 or exon 4 at c.117 mutations were retrieved, and only 1 NRAS exon 4 at c.146 mutation was detected. This present cohort is likely to represent most of the incident cases of metastatic colorectal adenocarcinomas arising in France over 6 months and is to our knowledge the largest population set genotyped for these genes in this condition. This is a unique opportunity to observe the frequency of RAS mutations regardless of most inclusion bias.

Dam C, Lund-Rasmussen V, Pløen J, et al.
Computed tomography assessment of early response to neoadjuvant therapy in colon cancer.
Dan Med J. 2015; 62(7) [PubMed] Related Publications
INTRODUCTION: Using multidetector computed tomography, we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer.
METHODS: Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment. All patients had histologically confirmed colon cancer, a T4 or T3 tumour with extramural invasion ≥ 5 mm and no distant metastases or peritoneal nodules. The patients were treated with oxaliplatin and capecitabine. In addition, those with no mutations in the KRAS, BRAF and PIK3CA genes were also treated with panitumumab. Before and after treatment, we measured the tumour diameter in two different planes, the extension of the extramural tumour invasion, and the number and size of enlarged lymph nodes.
RESULTS: The mean tumour length was 7.8 cm (95% confidence interval (CI): 5.3-10.4) at baseline and 4.34 cm (95% CI: 4.0-4.9) after treatment. The mean extramural tumour invasion was 10.6 mm (95% CI: 9.5-11.8) at baseline and 5.7 mm (95% CI: 4.7-6.7) after treatment. The mean number of enlarged lymph nodes was 4.1 (95% CI: 3.4-4.9) at baseline and 2.1 (95% CI: 1.4-2.7) after treatment. According to RECIST 1.1, 45% (95% CI: 34-57) of the patients had a response and 55% (95% CI: 43-67) had stable disease. None of the patients showed progressive disease.
CONCLUSION: Using CT, we demonstrated a significant reduction in tumour size, extramural tumour invasion, number and size of enlarged lymph nodes following neoadjuvant treatment.
FUNDING: not relevant.
TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT 01108107).

Karapetis CS, Maru D, Waring P, et al.
Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer.
Expert Rev Mol Diagn. 2015; 15(8):1033-48 [PubMed] Related Publications
The role of biomarker assessment in determining the best therapeutic options for patients with metastatic colorectal cancer has become increasingly complex and important. Biomarkers that predict the efficacy and/or toxicity of such treatments can affect medical decision making, leading to decreased harm and/or costs associated with treatment and improvements in therapeutic outcomes for patients. This review discusses traditional and emerging biomarkers of potential clinical utility for patients with metastatic colorectal cancer, current assays and methods used in clinical practice, technologies that have allowed the identification of new biomarkers and key considerations for oncologists and pathologists when determining appropriate biomarker evaluations to be undertaken for their patients.

Hutchinson RA, Adams RA, McArt DG, et al.
Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer.
J Transl Med. 2015; 13:217 [PubMed] Free Access to Full Article Related Publications
The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis.

Schmitt NC, Trivedi S, Ferris RL
STAT1 Activation Is Enhanced by Cisplatin and Variably Affected by EGFR Inhibition in HNSCC Cells.
Mol Cancer Ther. 2015; 14(9):2103-11 [PubMed] Article available free on PMC after 01/09/2016 Related Publications
Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at serine (S727) or tyrosine (Y701) residues. Cisplatin consistently increased the levels of p-S727-STAT1, and STAT1 siRNA knockdown attenuated cisplatin-induced cell death. EGFR stimulation also activated p-S727-STAT1 and p-Y701-STAT1 in a subset of cell lines, whereas EGFR inhibitors alone decreased levels of p-S727-STAT1 and p-Y701-STAT1 in these cells. Contrary to our hypothesis, EGFR inhibitors added to cisplatin treatment caused variable effects among cell lines, with attenuation of p-S727-STAT1 and enhancement of cisplatin-induced cell death in some cells and minimal effect in other cells. Using HNSCC tumor specimens from a clinical trial of adjuvant cisplatin plus the anti-EGFR antibody panitumumab, higher intratumoral p-S727-STAT1 appeared to correlate with worse survival. Together, these results suggest that cisplatin-induced cell death is associated with STAT1 phosphorylation, and the addition of anti-EGFR therapy to cisplatin has variable effects on STAT1 and cell death in HNSCC.

Chibaudel B, Bonnetain F, Tournigand C, et al.
STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.
BMC Cancer. 2015; 15:496 [PubMed] Article available free on PMC after 01/09/2016 Related Publications
BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials.
METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.
DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013.
TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Vera R, Alonso V, Gállego J, et al.
Current controversies in the management of metastatic colorectal cancer.
Cancer Chemother Pharmacol. 2015; 76(4):659-77 [PubMed] Related Publications
The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

Bertotti A, Sassi F
Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies.
Clin Cancer Res. 2015; 21(15):3377-83 [PubMed] Related Publications
Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts. Indeed, EGFR signals are crucial for the reconstitution of damaged mucosa in the context of acute inflammation, and their sustained activation is likely to turn into a pro-oncogenic cue during chronic inflammation. Although positive predictors of response to anti-EGFR antibodies remain unknown, multiple determinants of resistance have been described, including alterations interfering with antibody-receptor interaction, deregulation of parallel signaling pathways, and mutations in downstream transducers. These findings provide new opportunities for the optimization of therapeutic strategies based on drug combinations. However, the emerging notion that genetic interactions and compensatory mechanisms may affect-both positively and negatively-the efficacy of targeted therapies complicates the rational design of combinatorial approaches and implies a rethinking of the criteria required to prioritize laboratory findings for clinical validation in investigational trials.

Wainberg ZA, Drakaki A
The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors.
Expert Opin Biol Ther. 2015; 15(8):1205-20 [PubMed] Related Publications
INTRODUCTION: Use of both the vascular endothelial growth factor (VEGF) inhibitor bevacizumab and the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab as potential first-line therapies for patients with RAS-wild-type metastatic colorectal cancer presents clinicians with an important decision. We review clinical data evaluating first-line treatment with EGFR inhibitors. Additionally, by undertaking an integrated 'bench-to-bedside' approach, we provide potential models, testable hypotheses and biological rationales that might account for these clinical observations.
AREAS COVERED: A literature search encompassing PubMed and the ASCO/ESMO websites was undertaken in October 2014. Search terms included 'colorectal cancer', 'cetuximab', 'panitumumab' and 'bevacizumab'.
EXPERT OPINION: A number of clinical studies indicate a survival benefit for patients receiving EGFR inhibitors in combination with chemotherapy in the first-line setting, relative to both chemotherapy alone and VEGF inhibitors plus chemotherapy. Existing preclinical and clinical data suggest that a biological basis exists for providing RAS-wild-type patients with first-line EGFR inhibitors, followed by second-line VEGF inhibitors. More specifically, first-line treatment with EGFR inhibitors may elicit unique biological changes that sensitize tumors to subsequent lines of therapy; conversely, first-line treatment with VEGF inhibitors may elicit biological changes that desensitize tumors to subsequent lines of therapy.

Dawood S, Cristofanilli M
IBC as a Rapidly Spreading Systemic Disease: Clinical and Targeted Approaches Using the Neoadjuvant Model.
J Natl Cancer Inst Monogr. 2015; 2015(51):56-9 [PubMed] Related Publications
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, younger age of onset as compared with other cancers, local and distant metastases, and lower overall survival. The multidisciplinary management of IBC includes neoadjuvant systemic chemotherapy, surgery, radiotherapy, and hormonal therapy in hormone receptor-positive disease. Pathological complete response represents an important prognostic factor suggesting IBC as the ideal in-vivo model for therapeutic development. Molecular subtyping demonstrated higher frequency of basal-like an HER2 disease in IBC compared with non-IBC indicating the areas of novel therapeutic interventions. The prospective testing of HER2-targeted therapies (eg, trastuzumab and lapatinib) demonstrated the validity of this concept and the potential to change the outcome of this aggressive disease.

Braig F, März M, Schieferdecker A, et al.
Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer.
Oncotarget. 2015; 6(14):12035-47 [PubMed] Article available free on PMC after 01/09/2016 Related Publications
Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by next-generation sequencing ("tumor tissue" cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent "liquid biopsy" cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.

Baas JM, Krens LL, Bos MM, et al.
Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.
Anticancer Drugs. 2015; 26(8):872-7 [PubMed] Related Publications
Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.

Cannon TL, Kokon MA, Shafqat S, Deeken JF
RAS Mutations Beyond KRAS Exon 2: A Review and Discussion of Clinical Trial Data.
Curr Treat Options Oncol. 2015; 16(7):33 [PubMed] Related Publications
Opinion statement: The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer. Epidermal growth factor receptor (EGFR) inhibitors have been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations. Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry, as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors. However, expanded analyses of first-line metastatic trials reveal that other RAS mutations, such as other KRAS mutations in exons 3 and 4, along with NRAS mutations, are predictive of poor responses to EGFR inhibitors as well. Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor. Further clinical trials are required to determine the predictive impact of each of these individual mutations. To date, they have been analyzed in the aggregate. The addition of targeted therapy, bevacizumab or an EGFR inhibitor, to a chemotherapy backbone should be considered for all appropriate patients. The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition. The largest trial that compared bevacizumab with an EGFR inhibitor in the first line, CALGB/SWOG 80405, did not show a statistically significant difference between the two groups, making the use of bevacizumab, cetuximab, or panitumumab reasonable in the first line.

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