Panitumumab In Patients Research Articles

Preoperative Chemoradiation Therapy in Combination With Panitumumab for Patients With Resectable Esophageal Cancer: The PACT Study

Preoperative chemoradiation therapy (CRT) has become the standard treatment strategy for patients with resectable esophageal cancer. This multicenter phase 2 study investigated the efficacy of the addition of the epidermal growth factor receptor (EGFR) inhibitor panitumumab to a preoperative CRT regimen with carboplatin, paclitaxel, and radiation therapy in patients with resectable esophageal cancer. Patients with resectable cT1N1M0 or cT2-3N0 to -2M0 tumors received preoperative CRT consisting of panitumumab (6 mg/kg) on days 1, 15, and 29, weekly administrations of carboplatin (area under the curve [AUC] = 2), and paclitaxel (50 mg/m(2)) for 5 weeks and concurrent radiation therapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. Primary endpoint was pathologic complete response (pCR) rate. We aimed at a pCR rate of more than 40%. Furthermore, we explored the predictive value of biomarkers (EGFR, HER 2, and P53) for pCR. From January 2010 until December 2011, 90 patients were enrolled. Patients were diagnosed predominantly with adenocarcinoma (AC) (80%), T3 disease (89%), and were node positive (81%). Three patients were not resected due to progressive disease. The primary aim was unmet, with a pCR rate of 22%. Patients with AC and squamous cell carcinoma reached a pCR of 14% and 47%, respectively. R0 resection was achieved in 95% of the patients. Main grade 3 toxicities were rash (12%), fatigue (11%), and nonfebrile neutropenia (11%). None of the biomarkers was predictive for response. The addition of panitumumab to CRT with carboplatin and paclitaxel was safe and well tolerated but could not improve pCR rate to the preset criterion of 40%.

Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab.

This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.

Role of derived neutrophil lymphocyte ratio as a biomarker in advanced colorectal cancer

BackgroundThe discovery and validation of prognostic and predictive biomarkers in advanced colorectal cancer is crucial for the personalisation of therapy. Inflammation-based prognostic scores have been developed, including the neutrophil lymphocyte ratio (NLR), and the derived NLR (dNLR) calculated using a differential white cell count. The NLR has been assessed in several cancers; in a retrospective series of advanced colorectal cancer, higher NLR was associated with reduced survival and poorer outcomes with chemotherapy. We aimed to validate the usefulness of the dNLR as a prognostic and a predictive biomarker to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer. MethodsWe studied patients from a phase 3, open-label, randomised controlled trial that assessed the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer (PICCOLO trial). The prognostic analysis included all patients for whom dNLR data were available; a subset with KRAS wild-type tumours randomised to standard irinotecan with or without panitumumab was also analysed for predictive value. The dNLR was calculated from the prerandomisation blood count and categorised as high (≥2) or low (<2). Prognostic and predictive values of the dNLR were assessed with Cox's proportional hazard and logistic regression, adjusting for known prognostic factors in advanced colorectal cancer. Findings1159 patients were included in the prognostic analysis, and 444 in the predictive analysis. In multivariate analysis, high dNLR was independently associated with reduced overall survival compared with low dNLR (hazard ratio 1·59, 95% CI 1·32–1·78; p<0·001), the only other significant factor being poor performance status (p<0·001). High dNLR was also associated with reduced progression free survival (1·29, 1·13–1·47, p<0·001). In the predictive analysis, dNLR was not predictive of overall benefit with the addition of panitumumab to irinotecan. The main trial results showed that the benefit of panitumumab is confined to patients with no mutations in EGFR downstream pathways (KRAS, BRAF, NRAS, and PIK3CA), and in the subset of 323 patients in this all-wild-type category panitumumab had a more marked effect on tumour response rate in patients with low dNLR (odds ratio 7·4, p<0·001) than in those with high dNLR (3·7, p<0·001); however, interaction testing was not significant. InterpretationThe dNLR seems to offer the clinician useful prognostic information. Since this information can easily be calculated from routine clinical data, its integration into routine patient assessment should be considered after further validation. We did not demonstrate significant predictive value for anti-EGFR therapy, but our finding of higher response with panitumumab in patients with a low dNLR is hypothesis generating. Further investigation in datasets from randomised controlled trials and exploratory translational work are warranted. FundingCancer Research UK, Yorkshire Cancer Research.

Single Agent Panitumumab in Patients With Incurable Cutaneous Squamous Cell Carcinoma: A Single-Center Phase 2 Study: Non-Squamous Cell Malignancies of the Head and Neck (thyroid, skin cancers, salivary gland and sinus cancers)

The systemic options for incurable cutaneous squamous cell carcinoma (CSCC) remains limited. The emergence of targeted therapy in other malignancies has provided promising results. The objective of this study was to prospectively investigate the efficacy of single agent panitumumab in the treatment of incurable CSCC.

A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors

A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors

Successful Treatment with Panitumumab and Irinotecan in a Colorectal Cancer Patient with a Severe Hypersensitivity Reaction to Cetuximab

Infusion-related reactions resulting from administration of monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are well defined in the literature. Although these reactions occur more frequently with earlier generation antibodies such as cetuximab, which contains 34% murine protein, the risk of immunogenicity is still present with fully human and humanized antibodies. Panitumumab is the first fully human monoclonal antibody approved by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer. It is associated with a lower risk of hypersensitivity reactions and premedications are not routinely required. Because of the inherent differences in protein sequence between the two agents, patients who experience infusion reactions with cetuximab may tolerate panitumumab administration. There are however limited data on the safety of panitumumab in patients with prior infusion reactions to cetuximab. We report a case of a 62-year-old patient with metastatic colorectal cancer who was treated successfully with panitumumab and irinotecan after developing a grade 4 infusion reaction to cetuximab therapy. Treatment with panitumumab was initiated approximately five weeks after the single dose of cetuximab resulted in respiratory failure, cardiac arrest and intensive care management. The patient was premedicated prior to first and all subsequent doses. To date, the patient has not experienced any hypersensitivity reactions and continues to receive panitumumab in combination with chemotherapy with objective improvement in his overall condition. This case suggests that panitumumab maybe safely administered in patients with prior infusion reactions to cetuximab.

The SPECTRUM of findings in treatment options for recurrent/metastatic head and neck cancer

Evaluation of: Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label Phase 3 randomised trial. Lancet Oncol. 14(8), 697-710 (2013). In recent decades, significant progress has been achieved in the biological understanding of squamous cell carcinoma of the head and neck (SCCHN) and the role of human papillomavirus (HPV) has become more evident. The EGF receptor (EGFR) signaling pathway represents the main target of the new therapeutic agents currently in development and has proven to be efficacious in locally advanced SCCHN. The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is still unknown. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of SCCHN in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. The identification of novel tumor targets has stimulated the search for other anti-EGFR agents with a more favorable side-effect profile, such as aspanitumumab, but the SPECTRUM study failed to meet its primary end point, stipulating the need to test these agents in clinical trials with a more appropriate choice of study end point. Overall survival, considered a gold standard, may be difficult to interpret if treatment only takes place in a small subinterval of overall survival, therefore, progression-free survival should be used as a surrogate end point for regulatory approval.

A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer

KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases

Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver-only, metastatic colon cancer. Chemotherapy-naive patients with unresectable liver metastases from colon cancer with no other metastatic disease sites were enrolled. All patients received upfront therapy with XELOX plus panitumumab (P-XELOX) and were reevaluated for resectability every 4 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival, the percentage of patients whose disease became radically resectable, and the safety of the P-XELOX combination. A total of 49 patients were recruited, 35 of whom had wild-type KRAS (wtKRAS) and 14 of whom (who were enrolled before study amendment) had unknown (9 patients) or mutated (5 patients) KRAS mutational status. Forty-six patients were evaluable for response. After conversion P-XELOX therapy, the ORR in the general population was 54%, with 2 complete responses, 23 partial responses, and 14 cases of stable disease. In patients with wtKRAS, the ORR of the patients reached 65% (2 CRs and 19 PRs), which allowed 15 patients with initial unresectable liver metastasis to be reclassified as having resectable disease. Survival analysis demonstrated a median progression-free survival of 8.5 months and a median OS of 21.9 months. Patients who underwent surgery were found to have a significantly better OS when compared with those who did not undergo surgery (P < .001). Overall, toxicities were found to be predictable and manageable, with the most common being cutaneous, gastrointestinal, and neurologic toxicities. Conversion P-XELOX therapy yields high response and resectability rates for patients with metastatic colon cancer with extensive liver involvement.

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fluorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265. Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8-12·2) in the panitumumab group and 9·0 months (8·1-11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729-1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6-6·6) in the panitumumab group and 4·6 months (4·1-5·4) in the control group (HR 0·780, 95% CI 0·659-0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7-13·7] vs 8·6 months [6·9-11·1]; HR 0·73 [95% CI 0·58-0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3-12·9] vs 12·6 months [7·7-17·4]; 1·00 [0·62-1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47-1·04]). Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. Amgen Inc.

First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous KRAS wild type (WT) non-small cell lung cancer (NSCLC).

8062 Background: KRAS WT colorectal cancer (CRC) is responsive to the EGFR inhibitors panitumumab (P) and cetuximab. Phase III data suggest a small, but statistically significant overall survival (OS) advantage with cetuximab + chemotherapy in KRAS unselected NSCLC (Pirker, Lancet 2009); and phase I data suggest P alone has activity in non-CRC tumors including NSCLC (Weiner, Clin Ca Res. 2008). This single-arm phase II trial examined the safety and efficacy of P in combination with carboplatin (C) and pemetrexed (Pem) in patients (pts) with advanced non-squamous KRAS WT NSCLC. The addition of P was hypothesized to improve the median time-to-progression (TTP) from 3.6 months (mos) (historical) to 5.4 mos (1-sided α .10, 80% power). Methods: Pts with previously untreated, unresectable stage IIIB/IV non squamous KRAS WT NSCLC received P 9 mg/kg, Pem 500 mg/m2, and C AUC=6 IV day 1 every 21 days for 6 cycles, followed by P and Pem maintenance every 21 days until progressive disease or unacceptable toxicity. Responses were evaluated every 2 cycles per RECIST 1.1. KRAS mutation testing was performed centrally (DxS kit). Tissue was also collected for EGFR FISH testing. Results: 60 pts were enrolled; median age, 65 years; 58% female, ECOG PS 0-1 (98%), and prior adjuvant chemotherapy (10%). Median number of cycles was 5 (range 1-22). At a median follow-up of 8.7 mos, the median TTP was 6.2 mos (95% CI: 3.7, 9.5), PFS 6.2 mos (95% CI 3.0, 9.0), 1 year OS 65.5% (95% CI 44.8%, 80%). 23 pts (38%) had partial responses (PR); the disease control rate (PR + proportion with stable disease) was 68%. Treatment-related toxicity (TRT) included (all grades) nausea (38%), fatigue (30%), rash (30%), and mucositis (23%). Severe (grade 3/4) TRT in &gt; 2 pts included: thrombocytopenia (11%), neutropenia (7%), and dehydration (5%). There were no treatment-related deaths. EGFR mutation and FISH analyses will be presented. Conclusions: The addition of panitumumab to carboplatin and pemetrexed in the first-line treatment of advanced KRAS WT NSCLC was safe and well-tolerated; the median TTP of 6.2 mos met the primary endpoint. Definitive assessment of the value of panitumumab in this setting requires a randomized trial. Clinical trial information: NCT01042288.

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial

SummaryBackgroundEGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.MethodsIn this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.FindingsBetween June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).InterpretationAddition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.FundingAmgen, UK National Institute for Health Research Biomedical Research Centre.

Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer

The randomized first-line trials, including the CRYSTAL trial, the OPUS trial, and the PRIME trial, have demonstrated the significant efficacy of cetuximab or panitumumab in patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type tumors. The addition of an antiepidermal growth factor receptor (anti-EGFR)-directed monoclonal antibody to chemotherapy for these patients significantly improved progression-free survival, response rates, and R0 resection rates to a greater extent than overall survival compared with patients who received chemotherapy alone. However, 2 recent randomized phase 3 trials, the MRC COIN trial and the Nordic VII trial, reported an unexpected lack of benefit from the addition of cetuximab to chemotherapy in the first-line setting. In addition, recent retrospective analyses performed on a pooled data set from major clinical trials added more complexity, reporting an unexpected association of KRAS G13D mutation with a better clinical outcome compared with patients who had other KRAS mutations in the first-line and salvage settings, whereas the other independent analysis failed to demonstrate a benefit from panitumumab in patients with the same KRAS G13D mutation. The anti-EGFR monoclonal antibody-associated skin toxicity and the controversial strategies of management also are discussed. In this review, the authors analyze the previous randomized clinical trials and more critically re-evaluate recent trials and subgroup analyses to derive 3 factors that need to be taken into consideration regarding the addition of EGFR-directed monoclonal antibodies to chemotherapy: the preclinical data on mechanisms of action between chemotherapy and anti-EGFR antibodies along with mechanisms of resistance to anti-EGFR antibodies, the role of cross-over events in overall survival data, and the significant dose reductions of chemotherapeutic agents when combined with anti-EGFR agents.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

397 Early results of the pilot study with the anti-Epidermal Growth-Factor Receptor (EGFR) monoclonal antibody Panitumumab in patients (pts) with multi-relapsed or refractory squamous cell carcinoma (SCC) of the penis

397 Early results of the pilot study with the anti-Epidermal Growth-Factor Receptor (EGFR) monoclonal antibody Panitumumab in patients (pts) with multi-relapsed or refractory squamous cell carcinoma (SCC) of the penis

Retrospective cohort study on the safety and efficacy of panitumumab for patients with metastatic colorectal cancer: The HGCSG1002 study—Analysis of after cetuximab refractory.

541 Background: In the previous studies, panitumumab (Pmab) has been demonstrated the efficacy for patients with metastatic colorectal cancer (mCRC) in all treatment lines. It is still controversial about the efficacy of Pmab for patients that had progressed on prior cetuximab (Cmab), though there had been a few reports (from Metges et al. and Wadlow et al.) regarding the efficacy of Pmab after Cmab refractory or intolerance. To evaluate the efficacy and safety of Pmab in patients with cetuximab-refractory mCRC, in comparison with anti-EGFR antibody naïve patients (Cmab-naïve) and Cmab-refractory or intolerance patients (prior-Cmab). Methods: Two hundred patients with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the patients that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were administered Pmab monotherapy were included in this analysis. Results: Of 93 patients (44 prior-Cmab and 49 Cmab-naïve) were evaluated. There were no significant differences in the baseline characteristics of the patients in each group. The incidence of Grade 3 or higher any skin toxicities were higher in the Cmab-naïve (26.5.%) than in the prior-Cmab (11.4%). The overall response rate (RR) was not significantly difference (prior-Cmab/ Cmab-naïve, 9.1%/ 10.2%), but the disease control rate (DCR) was slightly higher in Cmab-naïve group (38.6%/ 55.1%, p=0.15). Progression free survival (PFS) and overall survival (OS) were follows: prior-Cmab/ Cmab-naïve, 2.8m/ 3.1m, 6.8m / 9.5m. There was a significant difference between the two groups in OS curve (p=0.04). Conclusions: Pmab was safely administered to heavily pretreated mCRC patients in daily practice. Although there were no significant differences in RR, DCS and PFS between prior-Cmab and Cmab-naïve, but the median OS was longer for the Cmab-naïve group compared with the prior-Cmab group. Therapeutic efficacies of Pmab for prior-Cmab patients did not comparable to those for Cmab-naïve patients. We are now performing a phase II trial on the efficacy of Pmab for Cmab-refractory mCRC patients.

Retrospective cohort study on the safety and efficacy of panitumumab for patients with metastatic colorectal cancer: The HGCSG1002 study—Analysis of adverse events.

554 Background: Panitumumab (Pmab) is a fully human monoclonal antibody specific to the epidermal growth factor receptor. It has been associated with very few infusion reactions, but has been pointed out more severe skin toxicity, compared to cetuximab which is a chimeric antibody.To evaluate the safety of Pmab for patients (pts) with metastatic colorectal cancer (mCRC) in daily clinical practice in Japan, retrospectively. Methods: Two hundred pts with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG1002 study). Adverse events were evaluated using Common Terminology Criteria for Adverse Events(CTCAE) Version 4.0. Results: Of 195 pts were able to evaluate for adverse events. Patients’ characteristics were as follows; male/female 112/83, median age 64 (range 40-82), ECOG performance status (0/1/2-) 103/71/21. Treatment line (1st/2nd/more than 3rd): 17/26/152. Grade 3 or higher adverse events related to Pmab were hypomagnesemia (11.5%), rash acneiform (14.3%), paronychia (4.6%). Adverse events accounted for 7.3% of pts discontinuation, but there were no treatment-related deaths. Grade 3 or higher hypomagenesaemia and rash acneiform were observed more often in more than 3rd line treatment, compared to 1st or 2nd line treatment (1st or 2nd/3rd-, 1/ 17, p=0.128, 2/26, p= 0.05). Conclusions: Severe hypomagnesemia was observed more often in daily practice in Japan, compared with previous reports. Grade 3 or higher hypomagnesemia and rash acneiform were observed more often in more than 3rd line setting, compared with 1st or 2nd line settings.

Targeted therapy for colorectal cancer resistance to EGF receptor antibodies and new trends

Colorectal cancer (CRC) remains a major health problem worldwide despite substan -tial advances in multimodal treatment. High quality comparative–effectiveness research has standardized surgery, radio-therapy and systemic chemotherapy. But there is still controversy on the selection of the best chemotherapeutic regimen and tailored targeted therapy. For exam-ple, there is currently a debate on whether testing for microsatellite instability and/or for the multigene assays, ColoPrint and Oncotype Dx, should be used for adju-vant chemotherapy decision in localized CRC. In the metastatic setting, decisions on cetuximab versus panitumumab for patients with

665TiP - Use Of Panitumumab in Patients with Recurrent or Progressive Colorectal Cancer - an Interim Analysis of the Vectis Study

ABSTRACT Registry Number 20080618 Background Panitumumab (Pmab; Vectibix®) is a fully human monoclonal antibody, which binds specifically to the human epidermal growth factor receptor (EGFr). Skin toxicity (ST), a pharmacological effect observed with EGFr inhibitors, appears in almost all patients (pts) treated with Pmab and is usually mild to moderate in severity. The VECTIS study was designed to determine the safety and efficacy of Pmab as monotherapy in daily practice with special reference to ST and its management. Methods This is an open-label, prospective, non-interventional study collecting data from pts from CEE countries, aged ≥18 years, who have EGFr expressing mCRC with wild type KRAS gene tumour status receiving Pmab monotherapy (6 mg/kg Q2W) after failure of chemotherapy regimens containing 5-FU, oxaliplatin and irinotecan. This interim analysis includes the data collected between 12/2008 and 06/2011 from pts in Hungary, Poland, and the CzechRepublic. The observation period was limited to 18 cycles. Results At the time of reporting, 177/205 (86.3%) enrolled pts have experienced a total of 266 ST events with an incidence rate (IR) (events per pt per year) of 3.47 (95% confidence interval [CI] = 3.07, 3.91); 15 pts experienced Grade 3 ST with an IR of 0.20 (95% CI = 0.11, 0.32) and no pts had ST Grade ≥4. Of the recorded ST events, 25.9% have resolved; 3.4% have resolved with consequences; 19.9% continue but are improving; and 50.8% have not resolved. Overall, 69.8% of pts required therapeutic measures for ST. Four serious Adverse Drug Reactions (ADRs) were reported. Of 6 deaths that occurred, none was related to Pmab. Four pts have stopped Pmab therapy due to ADRs including ST or other toxicity. Overall (N = 205) % (95% CI) ST Grade ≥ 2 (N = 112) % (95% CI) Tumor response 26.8 (20.9, 33.4) 30.4 (22.0, 39.8) Disease control rate 67.8 (60.9, 74.1) 70.5 (61.2, 78.8) Free from progression (18 cycles) 12.7 (8.5, 18.0) 13.4 (7.7, 21.1) A statistically significant positive correlation was observed between severity of ST and the best response (r = 0.13) as well as tumor response (r = 0.15). Conclusion In clinical practice, Pmab monotherapy appears to be well tolerated and effective in pts who have heavily pre-treated mCRC with wild-type KRAS status. This study is sponsored by Amgen GmbH CEE Headquarters. Disclosure R. Lakomy: Vectis study. W. Rogowski: Vectis study, Pegfilgrastim study. B. Piko: Vectis study, Pegfilgrastim study. C. Andras: Vectis study, Pegfilgrastim study, Amgen sponsored scientific event speaker. E. Molnar: employment possition Amgen, stock

Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer

Combination chemotherapy has proven beneficial in biliary tract cancer and further improvements may be achieved by individualizing treatment based on biomarkers and by adding biological agents. We report the effect of chemotherapy with panitumumab as first-line therapy for KRAS wild-type irresectable biliary tract cancer. Patients were treated with gemcitabine 1000 mg/m(2), oxaliplatin 60 mg/m(2), and panitumumab 6 mg/kg i.v. every 2 weeks followed by two daily administrations of capecitabine 1000 mg/m(2) in 7 days. During 22 months, 46 patients were included in a single institution. The primary end point, fraction of progression-free survival (PFS) at 6 months, was 31/42 [74%; 95% confidence interval (CI) 58% to 84%]. Forty-two patients had measurable disease. Response rate was 33% and disease control rate 86%. Median PFS was 8.3 months (95% CI 6.7-8.7 months) and median overall survival was 10.0 months (95% CI 7.4-12.7 months). Toxicity was manageable including eight cases of epidermal growth factor receptor-related skin adverse events of grade 2 or more. Marker-driven patient selection is feasible in the systemic treatment of biliary tract cancer. Combination chemotherapy with panitumumab in patients with KRAS wild-type tumors met the efficacy criteria for future testing in a randomized trial.