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Marc Peeters - One of the best experts on this subject based on the ideXlab platform.
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relationships between tumour response and primary tumour location and predictors of long term survival in patients with ras wild type metastatic colorectal cancer receiving first line Panitumumab therapy retrospective analyses of the prime and peak c
British Journal of Cancer, 2018Co-Authors: Marc Peeters, Timothy J Price, Julien Taieb, Michael Geissler, Fernando Rivera, Jeanluc Canon, George Pentheroudakis, Reija Koukakis, Peter Burdon, Salvatore SienaAbstract:Data from two trials of Panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival. Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed. A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with Panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with Panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with Panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival. First-line Panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to Panitumumab.
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final results and outcomes by prior bevacizumab exposure skin toxicity and hypomagnesaemia from aspecct randomized phase 3 non inferiority study of Panitumumab versus cetuximab in chemorefractory wild type kras exon 2 metastatic colorectal cancer
European Journal of Cancer, 2016Co-Authors: Timothy J Price, Stefano Cascinu, Paul Ruff, Anne L Thomas, Sergei Tjulandin, Tae Won Kim, Attili Satya Suresh, Xuesong Guan, Marc PeetersAbstract:Abstract Purpose The primary analysis of the ASPECCT study demonstrated that Panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive Panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m 2 ) followed by 250 mg/m 2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (Panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with Panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with Panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with Panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed Panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov, NCT01001377.
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analysis of kras nras mutations in a phase iii study of Panitumumab with folfiri compared with folfiri alone as second line treatment for metastatic colorectal cancer
Clinical Cancer Research, 2015Co-Authors: Marc Peeters, Timothy J Price, Kelly S Oliner, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Thierry Andre, Emily Chan, Florian LordickAbstract:Purpose: We evaluated the influence of RAS mutation status on the treatment effect of Panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of Panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). Experimental Design: Outcomes were from the study9s primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for Panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored Panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from Panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the Panitumumab–FOLFIRI group versus 10% in the FOLFIRI group. Conclusions: Patients with RAS mutations were unlikely to benefit from Panitumumab–FOLFIRI and the benefit–risk of Panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR. See related commentary by Salazar and Ciardiello, p. 5415
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Panitumumab versus cetuximab in patients with chemotherapy refractory wild type kras exon 2 metastatic colorectal cancer aspecct a randomised multicentre open label non inferiority phase 3 study
Lancet Oncology, 2014Co-Authors: Timothy J Price, Jin Li, Kathy Zhang, Stefano Cascinu, Marc Peeters, Paul Ruff, Atilli Satya Suresh, Anne L Thomas, Sergei Tjulandin, Swaminathan MurugappanAbstract:Summary Background The anti-EGFR monoclonal antibodies Panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of Panitumumab versus cetuximab in these patients. Methods For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive Panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m 2 ; 250 mg/m 2 once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0·55). The primary analysis included patients who received one or more dose of Panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with ClinicalTrials.gov, number NCT01001377. Findings Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received Panitumumab and 500 received cetuximab. For the primary analysis of overall survival, Panitumumab was non-inferior to cetuximab ( Z score −3·19; p=0·0007). Median overall survival was 10·4 months (95% CI 9·4–11·6) with Panitumumab and 10·0 months (9·3–11·0) with cetuximab (HR 0·97; 95% CI 0·84–1·11). Panitumumab retained 105·7% (81·9–129·5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3–4 was similar across treatment groups. Grade 3–4 skin toxicity occurred in 62 (13%) patients given Panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3–4 infusion reactions was lower with Panitumumab than with cetuximab (one [ vs nine [2%] patients), and the occurrence of grade 3–4 hypomagnesaemia was higher in the Panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab. Interpretation Our findings show that Panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3–4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment. Funding Amgen Inc.
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health related quality of life in patients with metastatic colorectal cancer treated with Panitumumab in first or second line treatment
British Journal of Cancer, 2011Co-Authors: Lee Bennett, Marc Peeters, Z Zhao, Beth Barber, Xiaolei Zhou, J Zhang, Jeffery Wiezorek, Jean-yves DouillardAbstract:Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without Panitumumab in the two trials. Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±Panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models. In the first-line trial, 576 patients with wild-type KRAS mCRC (284 Panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 Panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial. The addition of Panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.
Timothy J Price - One of the best experts on this subject based on the ideXlab platform.
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relationships between tumour response and primary tumour location and predictors of long term survival in patients with ras wild type metastatic colorectal cancer receiving first line Panitumumab therapy retrospective analyses of the prime and peak c
British Journal of Cancer, 2018Co-Authors: Marc Peeters, Timothy J Price, Julien Taieb, Michael Geissler, Fernando Rivera, Jeanluc Canon, George Pentheroudakis, Reija Koukakis, Peter Burdon, Salvatore SienaAbstract:Data from two trials of Panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival. Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed. A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with Panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with Panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with Panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival. First-line Panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to Panitumumab.
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Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC.
Future oncology (London England), 2018Co-Authors: Mark Mcgregor, Timothy J PriceAbstract:The humanized monoclonal antibody Panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for Panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of Panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of Panitumumab continues to evolve as understanding of sequencing of therapies grows. There is evidence for use as maintenance therapy and conversion therapy for unresectable liver metastases. Future research is likely to focus on biomarkers for improved patient selection and the development of novel therapeutic strategies to overcome resistance.
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final results and outcomes by prior bevacizumab exposure skin toxicity and hypomagnesaemia from aspecct randomized phase 3 non inferiority study of Panitumumab versus cetuximab in chemorefractory wild type kras exon 2 metastatic colorectal cancer
European Journal of Cancer, 2016Co-Authors: Timothy J Price, Stefano Cascinu, Paul Ruff, Anne L Thomas, Sergei Tjulandin, Tae Won Kim, Attili Satya Suresh, Xuesong Guan, Marc PeetersAbstract:Abstract Purpose The primary analysis of the ASPECCT study demonstrated that Panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive Panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m 2 ) followed by 250 mg/m 2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (Panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with Panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with Panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with Panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed Panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov, NCT01001377.
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Pharmacokinetic and pharmacodynamic evaluation of Panitumumab in the treatment of colorectal cancer
Expert opinion on drug metabolism & toxicology, 2015Co-Authors: Dainik Patel, Amanda R. Townsend, Timothy J PriceAbstract: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 pharmacodynami...
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analysis of kras nras mutations in a phase iii study of Panitumumab with folfiri compared with folfiri alone as second line treatment for metastatic colorectal cancer
Clinical Cancer Research, 2015Co-Authors: Marc Peeters, Timothy J Price, Kelly S Oliner, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Thierry Andre, Emily Chan, Florian LordickAbstract:Purpose: We evaluated the influence of RAS mutation status on the treatment effect of Panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of Panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). Experimental Design: Outcomes were from the study9s primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for Panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored Panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from Panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the Panitumumab–FOLFIRI group versus 10% in the FOLFIRI group. Conclusions: Patients with RAS mutations were unlikely to benefit from Panitumumab–FOLFIRI and the benefit–risk of Panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR. See related commentary by Salazar and Ciardiello, p. 5415
Salvatore Siena - One of the best experts on this subject based on the ideXlab platform.
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relationships between tumour response and primary tumour location and predictors of long term survival in patients with ras wild type metastatic colorectal cancer receiving first line Panitumumab therapy retrospective analyses of the prime and peak c
British Journal of Cancer, 2018Co-Authors: Marc Peeters, Timothy J Price, Julien Taieb, Michael Geissler, Fernando Rivera, Jeanluc Canon, George Pentheroudakis, Reija Koukakis, Peter Burdon, Salvatore SienaAbstract:Data from two trials of Panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival. Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed. A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with Panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with Panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with Panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival. First-line Panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to Panitumumab.
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Skin toxicity and quality of life during treatment with Panitumumab for RAS wild-type metastatic colorectal carcinoma: results from three randomised clinical trials
Quality of life research : an international journal of quality of life aspects of treatment care and rehabilitation, 2016Co-Authors: Reija Koukakis, F Gatta, Guy Hechmati, Salvatore SienaAbstract:Purpose Epidermal growth factor receptor inhibitors such as Panitumumab are associated with characteristic skin toxicities. We summarise data from three Panitumumab clinical trials to investigate the potential impact of skin toxicity on quality of life (QoL) in patients with metastatic colorectal cancer (mCRC).
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randomized phase iii trial of Panitumumab with infusional fluorouracil leucovorin and oxaliplatin folfox4 versus folfox4 alone as first line treatment in patients with previously untreated metastatic colorectal cancer the prime study
Journal of Clinical Oncology, 2010Co-Authors: Jean-yves Douillard, Salvatore Siena, Yves Humblet, Jim Cassidy, Josep Tabernero, Ronald Burkes, Mario Edmundo Barugel, Gyorgy Bodoky, David Cunningham, Jacek JassemAbstract:PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of Panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive Panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, Panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for Panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the Panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that Panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008Co-Authors: Federica Di Nicolantonio, Miriam Martini, Francesca Molinari, Andrea Sartore-bianchi, Sabrina Arena, Piercarlo Saletti, Sara De Dosso, Luca Mazzucchelli, Milo Frattini, Salvatore SienaAbstract:PURPOSE Cetuximab or Panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or Panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or Panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or Panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or Panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to Panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to Panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
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Wild-type KRAS is required for Panitumumab efficacy in patients with metastatic colorectal cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008Co-Authors: Rafael G. Amado, Marc Peeters, Eric Van Cutsem, Daniel J. Freeman, Salvatore Siena, Michael S. Wolf, Todd Juan, Robert Sikorski, Sid Suggs, Robert RadinskyAbstract:Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing Panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of Panitumumab on progression-free survival (PFS) differed by KRAS status. Results KRAS status was ascertained in 427 (92%) of 463 patients (208 Panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for Panitumumab and 7.3 weeks for BSC. Response rates to Panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for Panitumumab monotherapy.
Stefano Cascinu - One of the best experts on this subject based on the ideXlab platform.
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final results and outcomes by prior bevacizumab exposure skin toxicity and hypomagnesaemia from aspecct randomized phase 3 non inferiority study of Panitumumab versus cetuximab in chemorefractory wild type kras exon 2 metastatic colorectal cancer
European Journal of Cancer, 2016Co-Authors: Timothy J Price, Stefano Cascinu, Paul Ruff, Anne L Thomas, Sergei Tjulandin, Tae Won Kim, Attili Satya Suresh, Xuesong Guan, Marc PeetersAbstract:Abstract Purpose The primary analysis of the ASPECCT study demonstrated that Panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive Panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m 2 ) followed by 250 mg/m 2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (Panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with Panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with Panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with Panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed Panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov, NCT01001377.
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Panitumumab versus cetuximab in patients with chemotherapy refractory wild type kras exon 2 metastatic colorectal cancer aspecct a randomised multicentre open label non inferiority phase 3 study
Lancet Oncology, 2014Co-Authors: Timothy J Price, Jin Li, Kathy Zhang, Stefano Cascinu, Marc Peeters, Paul Ruff, Atilli Satya Suresh, Anne L Thomas, Sergei Tjulandin, Swaminathan MurugappanAbstract:Summary Background The anti-EGFR monoclonal antibodies Panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of Panitumumab versus cetuximab in these patients. Methods For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive Panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m 2 ; 250 mg/m 2 once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0·55). The primary analysis included patients who received one or more dose of Panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with ClinicalTrials.gov, number NCT01001377. Findings Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received Panitumumab and 500 received cetuximab. For the primary analysis of overall survival, Panitumumab was non-inferior to cetuximab ( Z score −3·19; p=0·0007). Median overall survival was 10·4 months (95% CI 9·4–11·6) with Panitumumab and 10·0 months (9·3–11·0) with cetuximab (HR 0·97; 95% CI 0·84–1·11). Panitumumab retained 105·7% (81·9–129·5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3–4 was similar across treatment groups. Grade 3–4 skin toxicity occurred in 62 (13%) patients given Panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3–4 infusion reactions was lower with Panitumumab than with cetuximab (one [ vs nine [2%] patients), and the occurrence of grade 3–4 hypomagnesaemia was higher in the Panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab. Interpretation Our findings show that Panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3–4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment. Funding Amgen Inc.
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Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer.
Core evidence, 2010Co-Authors: Rossana Berardi, Azzurra Onofri, Mirco Pistelli, Elena Maccaroni, Mario Scartozzi, Chiara Pierantoni, Stefano CascinuAbstract:Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of Panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for Panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, Panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by Panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with Panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of Panitumumab in the treatment of metastatic colorectal cancer in clinical practice.
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Gene Expression Profiles Can Predict Panitumumab Monotherapy Responsiveness in Human Tumor Xenograft Models
Neoplasia (New York N.Y.), 2013Co-Authors: Michael Boedigheimer, Daniel J. Freeman, P. Kiaei, Michael A. Damore, Robert RadinskyAbstract:Abstract Background Epidermal growth factor receptor (EGFR)-targeted agents have demonstrated clinical benefit in patients with cancer. Identifying tissue-of-origin-independent predictive biomarkers is important to optimally treat patients. We sought to identify a gene array profile that could predict responsiveness to Panitumumab, a fully human EGFR-binding antibody, using preclinical models of human cancer. Methods Mice bearing 25 different xenograft models were treated twice weekly with Panitumumab or immunoglobulin G2 control to determine their responsiveness to Panitumumab. Samples from these xenografts and untreated xenografts were arrayed on the Affymetrix human U133A gene chip to identify gene sets predicting responsiveness to Panitumumab using univariate and multivariate analyses. The predictive models were validated using the leave-one-group-out (LOO) method. Results Of the 25 xenograft models tested, 12 were responsive and 13 were resistant to Panitumumab. Unsupervised analysis demonstrated that the xenograft models clustered by tissue type rather than responsiveness to Panitumumab. After normalizing for tissue effects, samples clustered by responsiveness using an unsupervised multidimensional scaling. A multivariate selection algorithm was used to select 13 genes that could stratify xenograft models based on responsiveness after adjustment for tissue effects. The method was validated using the LOO method on a training set of 22 models and confirmed independently on three new models. In contrast, a univariate gene selection method resulted in higher misclassification rates. Conclusion A model was constructed from microarray data that prospectively predict responsiveness to Panitumumab in xenograft models. This approach may help identify patients, independent of disease origin, likely to benefit from Panitumumab.
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Augmentation of radiation response by Panitumumab in models of upper aerodigestive tract cancer
International journal of radiation oncology biology physics, 2008Co-Authors: Tim J. Kruser, Daniel J. Freeman, Robert Radinsky, Eric A. Armstrong, Amol J. Ghia, Shyhmin Huang, Deric L. Wheeler, Paul M. HarariAbstract:Purpose To examine the interaction between Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, and radiation in head-and-neck squamous cell carcinoma and non–small-cell lung cancer cell lines and xenografts. Methods and Materials The head-and-neck squamous cell carcinoma lines UM-SCC1 and SCC-1483, as well as the non–small-cell lung cancer line H226, were studied. Tumor xenografts in athymic nude mice were used to assess the in vivo activity of Panitumumab alone and combined with radiation. In vitro assays were performed to assess the effect of Panitumumab on radiation-induced cell signaling, apoptosis, and DNA damage. Results Panitumumab increased the radiosensitivity as measured by the clonogenic survival assay. Radiation-induced epidermal growth factor receptor phosphorylation and downstream signaling through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was inhibited by Panitumumab. Panitumumab augmented radiation-induced DNA damage by 1.2–1.6-fold in each of the cell lines studied as assessed by residual γ-H 2 AX foci after radiation. Radiation-induced apoptosis was increased 1.4–1.9-fold by Panitumumab, as evidenced by Annexin V-fluorescein isothiocyanate staining and flow cytometry. In vivo, the combination therapy of Panitumumab and radiation was superior to Panitumumab or radiation alone in the H226 xenografts ( p = 0.01) and showed a similar trend in the SCC-1483 xenografts ( p = 0.08). In vivo, immunohistochemistry demonstrated the ability of Panitumumab to augment the antiproliferative and antiangiogenic effects of radiation. Conclusion These studies have identified a favorable interaction in the combination of radiation and Panitumumab in upper aerodigestive tract tumor models, both in vitro and in vivo . These data suggest that clinical investigations examining the combination of radiation and Panitumumab in the treatment of epithelial tumors warrant additional pursuit.
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Panitumumab and cetuximab epitope mapping and in vitro activity
Journal of Clinical Oncology, 2008Co-Authors: Daniel J. Freeman, Jilin Sun, Randall Bass, Selam Ogbagabriel, Gary Elliott, K. Jung, Robert RadinskyAbstract:14536 Background: Panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), has anti- tumor activity as monotherapy in both preclinical models and clinical trials. The objective of this study was to identify the epitope on EGFR for Panitumumab and compare it to that of cetuximab, a chimeric anti-EGFR Ab. Methods: The extracellular domain of EGFR (amino acids 1–618) and domains I, II, III, IV individually were expressed to determine the domain on EGFR that was necessary for Panitumumab binding. Chromatography was used to compare the binding affinity of Panitumumab vs cetuximab. By flow cytometry and amino acid replacement scanning, the critical residues involved in Panitumumab and cetuximab binding for EGFR were determined. Using diffraction data from the Panitumumab Fab’2 and published data for cetuximab, crystal structure models of EGFR and the residues determined to be critical for Panitumumab or cetuximab binding were built. To evaluate in vitro activity, A549 NSCL...
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Wild-type KRAS is required for Panitumumab efficacy in patients with metastatic colorectal cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008Co-Authors: Rafael G. Amado, Marc Peeters, Eric Van Cutsem, Daniel J. Freeman, Salvatore Siena, Michael S. Wolf, Todd Juan, Robert Sikorski, Sid Suggs, Robert RadinskyAbstract:Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing Panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of Panitumumab on progression-free survival (PFS) differed by KRAS status. Results KRAS status was ascertained in 427 (92%) of 463 patients (208 Panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for Panitumumab and 7.3 weeks for BSC. Response rates to Panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for Panitumumab monotherapy.
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Epitope mapping and eludication of the mechanism of action of Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR)
Molecular Cancer Therapeutics, 2007Co-Authors: Daniel J. Freeman, Jilin Sun, Randall Bass, Ken Chong, Selam Ogbagabriel, Gary Elliott, Robert RadinskyAbstract:B121 Background: Understanding an antibody’s binding epitope may shed light on its mechanism of action (MOA). Panitumumab, a fully human monoclonal antibody directed against epidermal growth factor receptor (EGFR), has demonstrated anti-tumor efficacy as a monotherapy in both preclinical models and in clinical trials. The objective of this study was to identify the residues on EGFR that are critical for Panitumumab binding and to gain further information on the mechanism of action of Panitumumab. Methods: The extracellular region of EGFR (amino acids 1-618) was expressed as an avidin fusion protein in 293T cells and purified using biotin coated polystytene beads. Fusion proteins were used to determine the binding affinity of Panitumumab using BIAcore technology and were used as a control for further epitope mapping studies using a flow cytometry based assay. EGFR truncation mutations, including individual domains I, II, III and IV, were also expressed to determine the domain on EGFR that was necessary for Panitumumab binding. Replacement scanning was performed on solvent-accessibleamino acids in domain III (ligand binding domain) to further define the critical residues involved in Panitumumab binding. Using diffraction data from the Panitumumab Fab’2, the crystal structure of the EGFR and the residues determined to be critical for Panitumumab binding, a model for Panitumumab binding that minimize steric clashes was built. To evaluate the potential MOA, A549 NSCLC cells were treated with 20μg/ml of Panitumumab 1 hour prior to a 15 minute stimulation with known EGFR ligands (TGF-α, amphiregulin, epiregulin, HB-EGF, betacellulin and EGF). Inhibition of ligand-induced phosphorylation of EGFR was determined using a specific anti-pEGFR (pY1068) antibody. Results: The binding affinity of Panitumumab for the extracellular domain of EGFR was 50 pM by BIAcore. Further truncation analysis by flow cytometry narrowed the binding epitope of Panitumumab to domain III of the EGFR. Point mutations revealed that amino acids 349, 355, 412 and 438 were critical for Panitumumab binding. A 2.9 Angstrom crystal structure of the Panitumumab Fab’2 was solved. A model of the Panitumumab-EGFR complex was generated and predicts that the CDRs for both light and heavy chains of Panitumumab would be proximal to domain III of EGFR. In vitro studies determined that Panitumumab can inhibit receptor activation of all known EGFR ligands in A549 NSCLC tumor cells. Conclusion: From our model using the point mutation and crystal structure data, we determined that Panitumumab binds to surface exposed amino acids in the ligand binding domain of EGFR (domain III). Panitumumab inhibits all known EGFR ligands, resulting in inhibition of receptor activation.
