anti-EGFR Monoclonal Antibodies Panitumumab Research Articles

Efficacy and Safety of Panitumumab in Patients With RAF/RAS-Wild-Type Glioblastoma: Results From the Drug Rediscovery Protocol.

The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.

Panitumumab plus trifluridine/tipiracil as third-line anti-EGFR rechallenge therapy in chemo-refractory RAS WT metastatic colorectal cancer: The VELO randomized phase II clinical trial.

129 Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) inhibitors in chemo-refractory metastatic colorectal cancer (mCRC) is an emerging therapeutic approach. Trifluridine-tipiracil is approved for treatment of chemo-refractory mCRC patients. Methods: Chemo-refractory RAS WT mCRC patients, that had a major response (partial or complete response) to first-line chemotherapy plus an anti-EGFR monoclonal antibody and had an-anti-EGFR drug-free interval during second-line therapy of four or more months were randomized in a phase II trial to assess the addition of the anti-EGFR monoclonal antibody panitumumab to trifluridine-tipiracil as third-line rechallenge therapy. The primary endpoint was progression free survival (PFS). Baseline plasma was analyzed for circulating free tumor (ct) DNA by using Biocartis Idylla platform to detect mutations in KRAS, NRAS, BRAF ( V600E) and EGFRextracellular domain ( S492R). In 24 patients with baseline RAS/BRAF wild type (WT) ctDNA, Foundation One liquid CDx (324 gene profiling) was also performed before treatment and at disease progression. Results: 62 patients were treated with trifluridine-tipiracil (31 patients, arm A) or with trifluridine-tipiracil plus panitumumab (31 patients, arm B). As of September 16, 2022, 1 patient in arm A and 2 patients in arm B were on treatment. The primary endpoint was met. Median PFS (mPFS) was 4 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28-0.82; P = 0.007]. Baseline plasma RAS/BRAF WT ctDNA was found in 23/31 patients in Arm A and in 26/31 patients in Arm B. In this group, mPFS was 4.5 months in Arm B versus 2.6 months in Arm A (HR: 0.48; 95% CI 0.26-0.89; P = 0.019). Disease control (major responses plus stable disease) was higher for patients in Arm B compared to Arm A (81% versus 48%), whereas disease progression was the best response in 19% versus 52% patients, respectively. PFS rates at 6 and 12 months were 38.5% and 15.4% in arm B versus 13% and 0% in arm A. At disease progression, Foundation One liquid CDx detected several mutations within the EGFR pathway, which could correlate with cancer cell resistance to panitumumab. Conclusions: This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892 .

First-line anti-EGFR or anti-VEGF therapy, tumour sidedness, and survival: Results from the South Australian (SA) Metastatic Colorectal Cancer (mCRC) Registry.

42 Background: The anti-EGFR monoclonal antibodies panitumumab (Pmab) and cetuximab (Cmab) and the anti-VEGF antibody bevacizumab (bev) have demonstrated clinical efficacy in mCRC in combination with first-line chemotherapy. Clinical and molecular characteristics, such as primary tumour sidedness, RAS, BRAF and MMR status are prognostic and predictive biomarkers for response to treatment. Our aim was to compare the survival and tumour characteristics of patients receiving first-line chemotherapy and antibody combinations using the SA mCRC Registry. Methods: This real-world registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2006. We identified patients who had received first-line Pmab, Cmab or bev. Survival was analysed using the Kaplan-Meier method and log-rank test to compare outcomes based on primary tumour location. Results: Of the 5537 patients currently entered onto the registry, 1313 with RAS results available had received first-line anti-EGFR/VEGF antibodies and had colon tumour side recorded. The table summarises median overall survival (mOS) and patient characteristics. Survival was significantly shorter for those with right colon cancers (P < 0.001). There were more high-grade (P < 0.001), KRAS mutant (P = 0.004) and BRAF mutant (P = 0.036) tumours in those with right colon cancers, and a trend towards fewer curative liver resections (P = 0.059). There was no significant difference in mOS seen between Pmab, Cmab or bev for both left (P = 0.14) and right-sided (P = 0.88) primary tumours. Conclusions: There were more high-grade, BRAF and KRAS mutant patients with right colon tumours, and lower rates of liver resection, which may explain the significantly shorter mOS. The survival seen for Pmab and Cmab was almost identical for both right and left primary tumours. When comparing Pmab, Cmab and bev as first-line therapy, there was no significant difference in mOS for both left- and right-sided CRC. [Table: see text]

Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab\u2032)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab\u2032)2 \u2013 implications for a PET theranostic strategy

BackgroundEpidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab')2 of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, 177Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2.ResultsPanitumumab F(ab')2 were conjugated to DOTA and complexed to 64Cu or 177Lu in high radiochemical purity (95.6 ± 2.1% and 96.7 ± 3.5%, respectively) and exhibited high affinity EGFR binding (Kd = 2.9 ± 0.7 × 10− 9 mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [64Cu]Cu-DOTA-panitumumab F(ab')2 (5.5–14.0 MBq; 50 μg) or [177Lu]Lu-DOTA-panitumumab F(ab')2 (6.5 MBq; 50 μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [64Cu]Cu-DOTA-panitumumab F(ab')2 or microSPECT/CT with [177Lu]Lu-DOTA-panitumumab F(ab')2 but not with irrelevant [177Lu]Lu-DOTA-trastuzumab F(ab')2. Tumour uptake at 24 h p.i. of [64Cu]Cu-DOTA-panitumumab F(ab')2 [14.9 ± 1.1% injected dose/gram (%ID/g) and [177Lu]Lu-DOTA-panitumumab F(ab')2 (18.0 ± 0.4%ID/g) were significantly higher (P < 0.05) than [177Lu]Lu-DOTA-trastuzumab F(ab')2 (2.6 ± 0.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [177Lu]Lu-DOTA-panitumumab F(ab')2 based on the BOD of [64Cu]Cu-DOTA-panitumumab F(ab')2 compared to those estimated directly from the BOD of [177Lu]Lu-DOTA-panitumumab F(ab')2 except for the liver and whole body which were modestly underestimated by [64Cu]Cu-DOTA-panitumumab F(ab')2. Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [177Lu]Lu-DOTA-panitumumab F(ab')2 predicted that a 2 cm diameter HNSCC tumour in a patient would receive 1.1–1.5 mSv/MBq and the whole body dose would be 0.15–0.22 mSv/MBq.ConclusionA PET theranostic strategy combining [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 is feasible. RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.

Abstract 1057: Combination of the KRASG12C inhibitor sotorasib with targeted agents improves anti-tumor efficacy in KRAS p.G12C cancer models

Abstract KRAS is the most frequently mutated oncogene in cancer and encodes a key signaling protein in tumors. The p.G12C mutation of KRAS is present in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer, and 2% of other solid tumors. Sotorasib (formerly known as AMG 510), the first KRASG12C inhibitor to reach clinical testing in humans, has demonstrated evidence of clinical activity as a single agent in patients with non-small cell lung (NSCLC), colorectal (CRC), endometrial, and appendiceal carcinoma. Preclinically, sotorasib has shown significant tumor growth inhibition as a single agent in multiple CDX and PDX models. The clinically-validated strategy of combining multiple inhibitors in the MAPK pathway suggests that combination strategies could yield even better outcomes for patients. Specifically, the combination of sotorasib and other inhibitors in the MAPK and AKT signaling pathways might further enhance tumor cell killing and overcome potential resistance. To test this hypothesis, in vitro combination experiments were conducted in multiple KRAS p.G12C cell lines with combination matrices of sotorasib and inhibitors of HER kinases, EGFR, SOS1, SHP2, MEK, PI3K, or mTOR, as well as an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). The combination of sotorasib with multiple agents resulted in robust synergistic cell killing of KRAS p.G12C tumor cells in vitro. To understand whether these observations translated in vivo, we assessed combinations of sotorasib with a SHP-2 inhibitor or a HER kinase inhibitor in pharmacodynamic assays and efficacy models in tumor xenografts. Consistent with the synergy observed in vitro, sotorasib in combination with a HER kinase inhibitor (afatinib) or a SHP2 inhibitor (RMC-4550) in vivo resulted in enhanced inhibition of MAPK signaling as measured by p-ERK in NCI-H358 tumors. In efficacy studies using the NCI-H358 xenograft model, significantly enhanced anti-tumor activity was observed with a minimally efficacious dose of sotorasib in combination with afatinib, RMC-4550, or a CDK4/6 inhibitor (palbociclib). Furthermore, enhanced anti-tumor activity was observed with sotorasib in combination with a MEK inhibitor or with the anti-EGFR monoclonal antibody panitumumab in a CRC KRAS p.G12C PDX model. Taken together, these data support the clinical evaluation of combination treatment of sotorasib with analogous agents in patients with KRAS p.G12C tumors. Citation Format: Karen Rex, Anne Y. Saiki, Tyler Holt, Alla Verlinsky, Patricia L. McElroy, Tao Osgood, Ji-Rong Sun, Marwan G. Fakih, Upendra P. Dahal, Bernd Bruenner, Victor J. Cee, Brian A. Lanman, Jude Canon, J. Russell Lipford. Combination of the KRASG12C inhibitor sotorasib with targeted agents improves anti-tumor efficacy in KRAS p.G12C cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1057.

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With or Without Panitumumab in Patients With Advanced Urothelial Carcinoma: Multicenter, Randomized, French Unicancer GETUG/AFU 19 Study

Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients with advanced, treatment-naïve, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers

ObjectiveEpidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN)...

Abstract 564: Identification of biomarkers predictive of response to panitumumab combined with neoadjuvant chemotherapy for primary inflammatory breast cancer

Abstract Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer, and there are no FDA-approved targeted therapies specific for IBC. We recently completed a single-arm phase II study of neoadjuvant therapy with the humanized anti-EGFR monoclonal antibody panitumumab (PmAb), nab-paclitaxel, and carboplatin followed by 5-fluorouracil, epirubicin, and cyclophosphamide in patients with newly diagnosed HER2-negative IBC (N = 40), which produced the highest pathologic complete response (pCR) rate (47%) ever observed in patients with triple-negative IBC (TN-IBC; negative for estrogen receptor, progesterone receptor, and HER2; N = 19). In the work described here, we aimed to identify biomarkers predictive of response of IBC to this combination therapy. We used immunohistochemical staining to examine the expression of key molecules involved in EGFR signaling, which regulates cancer stem cells and epithelial-mesenchymal transition in IBC, including EGFR, phosphorylated EGFR (pEGFR), E-cadherin, vimentin, COX-2, and Nodal, in paired tumor samples obtained before and after the first dose of PmAb in our phase II trial. Our data showed that the expression of pEGFR (P = .05) and COX-2 (P = .05) in pre-PmAb tissues marginally correlated with pCR; the change of pEGFR expression (P = .09) between pre-PmAb and post-PmAb samples showed a trend toward correlation with pCR. We conducted RNA-seq on 13 pairs of tumor biopsy specimens obtained before and after the first dose of PmAb. Analysis of all samples did not identify any candidate genes with significant changes after PmAb treatment. In the TN-IBC samples, we identified 2 genes (POU3F3 and EGR1) that were significantly downregulated and 4 genes (BBOX1, GLYATL2, MUCL1, and LCN2) that were significantly upregulated after PmAb treatment, but we did not identify any gene whose change in expression predicted pCR status, possibly because the small sample size of the non-pCR group (N = 2) limits the statistical power. We validated the change in expression of EGR1, MUCL1, and LCN2 after PmAb treatment in SUM149 IBC cells. In the hormone-receptor-positive, HER2-negative tumor samples, we identified 19 genes that were significantly downregulated and 10 genes that were significantly upregulated after PmAb treatment. These genes function in cellular movement, cell morphology, cell-to-cell signaling and interaction, molecular transport, and the cell cycle. Our results suggest potential roles of pEGFR and COX-2 expression at baseline and PmAb-modulated pEGFR, EGR1, MUCL1, and LCN2 expression in predicting PmAb response. Validation of these biomarker candidates and studies of the mechanisms by which they affect IBC response are ongoing. Citation Format: Xiaoping Wang, Naoko Matsuda, Bora Lim, Savitri Krishnamurthy, Juhee Song, Yu Shen, Wenhui Wu, Jianhua Hu, Wendy A. Woodward, James M. Reuben, Anthony Lucci, Debu Tripathy, Vicente Valero, Naoto T. Ueno. Identification of biomarkers predictive of response to panitumumab combined with neoadjuvant chemotherapy for primary inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 564.

Anti-EGFR monoclonal antibody panitumumab for the treatment of patients with metastatic colorectal cancer: an overview of current practice and future perspectives

ABSTRACTIntroduction: Targeted agents alone or in combination with chemotherapy are current standard of treatment for metastatic colorectal cancer (mCRC). Panitumumab is a fully human monoclonal antibody which inhibits the epidermal growth factor receptor (EGFR). It is currently approved in combination with chemotherapy in first- and second-line and as a monotherapy in chemorefractory patients. RAS gene mutations confer resistance to anti-EGFR agents; thus, panitumumab is restricted to the treatment of RAS wild-type (WT) tumors.Areas covered: This review explores the available data on panitumumab and presents new perspectives on predictive markers of anti-EGFR efficacy including primary tumor sidedness and BRAF mutations. Other details covered include panitumumab’s mechanism of action, pharmacokinetics, pharmacodynamics and safety aspects of the therapy as well as mechanisms of secondary resistance and future prospects of treatment in different settings.Expert opinion: Panitumumab has significantly added to the treatment armamentarium for RAS WT mCRC. The effort spent in identifying predictive biomarkers of panitumumab efficacy has been of pivotal importance to development of the molecular selection of patients with mCRC. Primary and secondary resistance, however, still represent important issues. Novel strategies to overcome those issues are currently underway with promising results which highlight the potential use of panitumumab in combination with other targeted agents in the future.

Abstract A52: Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P)

Abstract Background: Several molecular alterations drive acquired resistance to anti-EGFR therapies in pts with KRAS WT mCRC. We designed a clinical trial to identify and treat MET amplification (amp), a well described driver of acquired EGFR resistance. Methods: Pts with KRAS WT mCRC were enrolled in 3 cohorts: 1) C+P Dose Finding (Dose Find): 3+3 design to determine the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of C+P; 2) C+P Expansion (Exp): to define the safety, tolerability and activity of C+P; and 3) MET amplified monotherapy (MET Mono): to determine the response rate of C alone in pts with prospectively identified MET amp/ EGFR refractory mCRC. Response assessment occurred every 2 months with computed tomography (CT) using RECIST criteria, version 1.1. cfDNA was collected at baseline and each restaging until progression. In the C+P Dose Find and Exp cohorts, peripheral blood was retrospectively sequenced for 54 gene mutations (mut) and focal amplifications, including MET (Guardant Health, Inc.). MET expressing circulating tumor cells (CTCs) were captured utilizing nanomagnetic particles conjugated to an antibody targeting extracellular MET (Janssen R&amp;D, LLC). Genomic amp was tested in tumor tissue using next generation sequencing (NGS) or FISH. These data allowed subgroup and individual pt profiling. Results: There were no dose limiting toxicity (DLT) events at the RPTD (C 60mg PO daily and P 6 mg/kg IV Q2 weeks) in the Dose Find cohort (n = 6). Assessment of treatment response in C+P cohorts: As of 7/21/2015, 13 pts were treated at the RPTD. 3 pts had not yet received response assessment; 10 pts (6 Dose Find; 4 Exp) were evaluable for response. 8/10 evaluable pts had failed prior anti-EGFR therapy. 6/10 had reduction in RECIST lesions (2/2 EGFR naïve; 4/8 EGFR refractory). Median change was -10% (range -40% to +18%). 2/2 evaluable pts with MET amp cfDNA had a reduction in target lesions (both EGFR refractory). 7/10 had a decrease in tumor marker (CEA). Median CEA change was -39% (range -86% to +103%). Baseline cfDNA profiling in C+P and MET Mono cohorts: 13 pts with EGFR refractory mCRC (6 Dose Find; 3 Exp; 4 MET mono) had baseline cfDNA profiling. 4/13 BRAF mut (2/4 subclonal), 3/13 KRAS mut (2/3 subclonal), 1/13 NRAS mut (0/1 subclonal), 3/13 HER2 amp (3/3 confirmed in tissue), 4/13 MET amp (0/2 in tissue; 2 not tested). Pt examples: One subject (EGFR refractory) had a lymph node biopsy 3 months prior to C+P that revealed no MET amp by NGS (Foundation Medicine). Pre-treatment cfDNA revealed MET amp. Treatment with C+P resulted in a partial response (-40% in RECIST lesions). MET amp was no longer detected in cfDNA at first restaging. A second subject had MET amp in pre-treatment cfDNA. MET-expressing CTCs were captured from peripheral blood. Single cell FISH on CTCs-but not archival tissue-confirmed MET amp. Conclusions: This ongoing phase I/II study demonstrates the feasibility of: 1) using cfDNA to detect MET amp in pts with EGFR refractory mCRC, even when archival tissue is negative; and 2) capturing MET-expressing CTCs to confirm MET amp. Preliminary clinical results support prospective cfDNA screening to identify and treat pts with EGFR refractory/ MET amp mCRC. Citation Format: John H. Strickler, Tian Zhang, Andrew J. Armstrong, Donna Niedzwiecki, Hope E. Uronis, Michael A. Morse, S. Yousuf Zafar, Shiao-Wen D. Hsu, Christy C. Arrowood, Rebecca Nagy, AmirAli Talasaz, Richard Lanman, Sherri Haley, Herbert I. Hurwitz. Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A52.

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

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. 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. 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 [<0.5%] patient 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. 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.

Molecular imaging reveals trastuzumab-induced epidermal growth factor receptor downregulation in vivo.

Previous in vitro studies demonstrated that treating tumors expressing both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 with trastuzumab resulted in increased EGFR homodimerization and subsequent rapid downregulation of EGFR. We investigated whether molecular imaging using near-infrared fluorescence (NIRF) imaging and PET probes could sensitively detect trastuzumab-induced EGFR downregulation in vivo. The F(ab')2 antibody fragment PaniF(ab')2 was generated by digesting the anti-EGFR monoclonal antibody panitumumab. PaniF(ab')2 was labeled with either a NIRF dye or (68)Ga, and optical imaging and small-animal PET imaging of Dye-PaniF(ab')2 and (68)Ga-PaniF(ab')2, respectively, were performed in HT-29 tumor-bearing nude mice treated with trastuzumab or untreated control. Longitudinal NIRF imaging studies revealed significantly reduced tumor uptake of Dye-PaniF(ab')2 on days 5 and 7 in trastuzumab-treated HT-29 tumors, compared with control. Western blotting confirmed the downregulation of EGFR after treatment with trastuzumab. Small-animal PET on day 5 after trastuzumab treatment also demonstrated decreased (68)Ga-PaniF(ab')2 uptake in trastuzumab-treated HT-29 tumors. The tumor uptake value of (68)Ga-PaniF(ab')2 obtained from PET imaging had an excellent linear correlation with the uptake value measured using biodistribution. The downregulation of EGFR induced by trastuzumab treatment could be detected noninvasively using optical and PET imaging. This molecular imaging strategy could provide a dynamic readout of changes in the tumor signaling and may facilitate the noninvasive monitoring of the early tumor response to drug treatment.

SP027 RAS mutations as markers of resistance for colorectal cancer patients treated with the anti-EGFR monoclonal antibody panitumumab

SP027 RAS mutations as markers of resistance for colorectal cancer patients treated with the anti-EGFR monoclonal antibody panitumumab

KRAS Mutation Testing in Human Cancers: The Pathologist's Role in the Era of Personalized Medicine

A number of studies have shown that although antiepidermal growth factor receptor (EGFR) monoclonal antibodies are effective treatments for metastatic colorectal cancer (mCRC), only patients with wild-type KRAS tumors derive clinical benefit from these therapies. The anti-EGFR monoclonal antibodies panitumumab and cetuximab are approved in the United States for treatment of mCRC refractory to chemotherapy but are not recommended for use in patients with mutations in KRAS codons 12 or 13. Similarly, panitumumab is approved for the treatment of mCRC only in patients with wild-type KRAS in Europe and Canada. It is clear that KRAS mutational analysis will become an important aspect of disease management in patients with mCRC. Consequently, it will be important for pathologists and oncologists to develop and agree on standardized KRAS testing and reporting procedures to ensure optimum patient care. Pathologists will be central to this process because of their crucial role in selecting appropriate tumor specimens for testing, choosing the molecular diagnostic laboratory to be used, assisting in the selection of a suitable KRAS test, and interpreting the results of KRAS mutational analysis. Guidelines for KRAS testing that address these and other important points of consideration have recently been proposed in the United States and the European Union.

KRAS Mutational Status as a Predictor of Epidermal Growth Factor Receptor Inhibitor Efficacy in Colorectal Cancer

Inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated promising potential in the treatment of advanced colorectal cancer. However, a proportion of patients do not respond to therapy with EGFR inhibitors, and therefore, there has been interest in identifying those patients most likely to benefit from therapy with these agents. KRAS, a member of the RAS family of signaling proteins, plays an important role in EGFR-mediated regulation of cellular proliferation and survival. Although there is still some debate regarding the prognostic importance of KRAS mutations in patients with metastatic colorectal cancer, several recent phase 2 and 3 studies have identified the presence of mutations at codons 12 and 13 of KRAS as predictors of poor response to the anti-EGFR monoclonal antibodies panitumumab and cetuximab. Patients with wild-type KRAS were found to have significantly better progression-free survival, overall survival, and/or objective response rate compared with patients harboring KRAS mutations. As a result, there has been growing interest in the development of KRAS mutational status as a biomarker for predicting patient response to EGFR-targeted therapy. Screening colorectal tumors for the absence of KRAS mutations may help identify patients most likely to benefit from anti-EGFR therapies.

Determinants of RASistance to Anti–Epidermal Growth Factor Receptor Agents

Determinants of <i>RAS</i>istance to Anti–Epidermal Growth Factor Receptor Agents