Coexpression of matrix metalloproteinase-7 (MMP7) and phosphorylated insulin growth factor receptor I (pIGF-IR) as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4063-4063
Author(s):  
C. Horndler ◽  
R. Gallego ◽  
V. Alonso ◽  
V. Alonso ◽  
P. Escudero ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Target Population ◽  
Median Number ◽  
Double Positive ◽  
Insulin Growth Factor ◽  
Mutational Status ◽  
Matrix Metalloproteinase 7 ◽  
Third Line

4063 Background: IGF-IR is supposed to have anti-apoptotic and mitogenic properties in colorectal cancer and by transactivation can promote EGFR phosphorylation. MMP-7 is produced by colorectal cancer cells and by degrading IGFBP-3 can activate IGF-IR. Methods: We retrospectively investigated the role of pIGF-IR immunoreactivity (IHC) (Rubini) and MMP-7 IHC in primary CRC or metastases, to predict response rate (RR), progression free survival (PFS) and overall survival (OS) in ACRC patients (pts) treated with either cetuximab or panitumumab as second or third line therapy. RAS mutational status of codons 12/13 was determined using quantitative PCR-based assay. CT scans were done every 1.5–2 months (m) until progressive disease. Results: A total of 99 pts with available tissue from 168 pts with ACRC treated with anti-EGFR therapy in 4 Spanish Institutions, were analysed for RAS mutational status, pIGF-1R and MMP-7. There were no major differences in RR (18.8 vs 16%), PFS [3.3 vs. 3.1 months (m)] and OS (7.7 vs. 7m) between the whole and selected cohort. Fifty-seven (57.6%) pts were male, the median age was 62 (range 34–79) years, the median number of previous chemotherapy lines was 2 (range 1–3) and PS was distributed as follow: PS0, 17 (17.2 %) pts; PS1, 66 (66.7%) pts and PS2, 16 (16.2%) pts. Expression of MMP-7 and pIGF-1R were observed in 48 (48.5%) and 52 (52.5%) pts respectively. Co-expression of MMP-7 and pIGF-1R [Double Positive (DP)] was observed in 26 (26.3 %) pts and in 16 (24%) out of 66 RAS wild-type (WTRAS) pts. There was no association between RAS mutational status and DP (p=0.52). DP progressed more than non-DP pts both in the overall sample (73 vs. 43%, p=0.028) and in WTRAS pts (75 vs. 32%, p=0.011). In the subset of WTRAS pts, DP pts also have a poorer OS: 6.4 (95% CI 5.8–7.1) m vs. 8.6 (95%CI 6.0–11.3) m (p=0.005), and a trend for worse PFS 2.7 vs 4.0 m (p=0.11). Conclusions: Co-expression of pIGF-1R and MMP7 is associated with resistance to anti- EGFR therapy in WTRAS pts. Our study suggests that pts with WTRAS and DP could be a target population to assay new anti-IGF-1R compounds. No significant financial relationships to disclose.

Incidence and patterns of phospho insulin growth factor receptor-1 (pIGF-1R) and matrilysin (MMP7) expression in metastatic colorectal cancer (mCRC), and correlation with KRAS status: A prospective evaluation in the PULSE trial—A GEMCAD study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14041-e14041
Author(s):  
Vicente Alonso ◽  
Carlos Fernandez-Martos ◽  
Marta Martin ◽  
Antonieta Salud ◽  
Jose Carlos Mendez ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Growth Factor Receptor ◽  
First Line ◽  
Double Positive ◽  
Exon 2 ◽  
Insulin Growth Factor ◽  
First Line Therapy ◽  
Mutational Status ◽  
Kras Status ◽  
Insulin Growth Factor Receptor

e14041 Background: MMP7 can activate IGF-1R by IGF release due to IGFBP degradation. Activation of IGF-1R can contribute to EGFR resistance by transactivation. We previously described that concomitant expression of p-IGF-1R and MMP7 (Double positive; DP), correlates with poor prognosis, in KRAS WT patients (pts) treated with anti-EGFR compounds (Horndler el al, 2011). Therefore we designed a prospective clinical trial to validate DP as a marker of resistance in KRAS WT pts treated in first-line therapy with FOLFOX-6 plus panitumumab. Methods: mCRC pts in the ongoing prospective PULSE trial (NCT0128833) were prospectively evaluated for p-IGF-1R (p-1316), MMP7 expression and KRAS mutational status. Pts defined as DP should express MMP7 (++ or +++ intensity in >66% of tumor cells) and p-IGF-1R (++ or +++ intensity in >66% of tumor cells). KRAS pts with mutations at exon 2 were excluded. The study was designed to include 40 pts in the two groups (DP vs non-DP) to detect a Hazard ratio difference in PFS of <0.5 (DP vs non-DP) with 80% power. Results: From November 2010 to December 2011, 113 consecutive pts were screened from 24 Spanish Institutions. 54 KRAS WT (40 pts non-DP and 14 DP) have been included. The non-DP arm has being recently closed for inclusion, due to pre-planned complete accrual. Among DP pts, 27% were KRAS WT and 30% KRAS mutant; p=0.63. 48% of cases were positive for p-IGF-1R. Phospho-IGF-1R positive cases had different patterns of staining: peri-nuclear in 76%, 11% nuclear and only 13% membrane-apical staining. These patterns do not differ between KRAS WT; (n=70) and KRAS mutant pts (n=43) (p=0.60). Tumors with positive p-IGF-1R expression, independently of the pattern, have higher MMP7 co-expression (59%) compared with negative cases (13%) (p<0.0001). Conclusions: MMP7 contributes to activate IGF-1R pathway in pts with mCRC. Internalization of the activated IGF-1R, could explain in part, the lack of efficacy of IGF-1R inhibitors in mCRC clinical trials.

scholarly journals Efficacy of Anti-EGFR in Microsatellite Instability Metastatic Colorectal Cancer Depending on Sporadic or Familial Origin

2020 ◽  
Author(s):  
Aziz Zaanan ◽  
Julie Henriques ◽  
Romain Cohen ◽  
David Sefrioui ◽  
Camille Evrard ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Methylation Status ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mutational Status ◽  
Repair Protein ◽  
Epidermal Growth ◽  
A Prospective Study

Abstract Anti-epidermal growth factor receptor (EGFR) efficacy in patients with microsatellite instability (MSI) metastatic colorectal cancer (mCRC) according to sporadic vs familial origin is unknown. We retrospectively analyzed 128 patients with MSI mCRC treated with first-line chemotherapy ± anti-EGFR. Among them, 61 and 67 patients were respectively categorized as familial and sporadic based on mismatch repair protein immunostaining, BRAF mutational status, and MLH1 promoter methylation status. We observed that addition of anti-EGFR to chemotherapy was associated with a statistically significant improvement of progression-free survival for familial (median = 5.0 vs 10.2 months, hazard ratio [HR] = 0.47, 95% confidence interval [CI] = 0.23 to 0.94; P = .03) but not for sporadic (median = 4.4 vs 5.4 months, HR = 0.80, 95% CI = 0.39 to 1.60; P = .52) MSI mCRC patients. In multivariate analysis, the survival benefit of adding anti-EGFR to chemotherapy remained statistically significant for familial MSI cases (P = .04). These findings deserve to be confirmed in a prospective study and could help decision making in MSI mCRC without access or resistant to immunotherapy.

scholarly journals Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

2008 ◽  
Vol 26 (33) ◽  
pp. 5352-5359 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robert G. Maki ◽  
Christopher L. Corless ◽  
Cristina R. Antonescu ◽  
Amy Harlow ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Clinical Activity ◽  
Wild Type ◽  
Mutational Status ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11 ◽  
The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

scholarly journals Long Term Real-World Outcomes of Trifluridine/Tipiracil in Metastatic Colorectal Cancer—A Single UK Centre Experience

2021 ◽  
Vol 28 (3) ◽  
pp. 2260-2269
Author(s):  
Daniel Tong ◽  
Lei Wang ◽  
Jeewaka Mendis ◽  
Sharadah Essapen
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Real World ◽  
Systemic Treatment ◽  
Progression Free Survival ◽  
Median Number ◽  
Current Data ◽  
Real World Data

In the UK, Trifluridine-tipiracil (Lonsurf) is used to treat metastatic colorectal cancer in the third-line setting, after prior exposure to fluoropyrimidine-based regimes. Current data on the real-world use of Lonsurf lack long-term follow-up data. A retrospective evaluation of patients receiving Lonsurf at our Cancer Centre in 2016–2017 was performed, all with a minimum of two-year follow-up. Fifty-six patients were included in the review. The median number of cycles of Lonsurf administered was 3. Median follow-up was 6.0 months, with all patients deceased at the time of analysis. Median progression-free survival (PFS) was 3.2 months, and overall survival (OS) was 5.8 months. The median interval from Lonsurf discontinuation to death was two months, but seven patients received further systemic treatment and median OS gained was 12 months. Lonsurf offered a slightly better PFS but inferior OS to that of the RECOURSE trial, with PFS similar to real-world data previously presented. Interestingly, 12.5% had a PFS > 9 months, and this cohort had primarily left-sided and RAS wild-type disease. A subset received further systemic treatment on Lonsurf discontinuation with good additional OS benefit. Lonsurf may alter the course of disease for a subset of patients, and further treatment on progression can be considered in carefully selected patients.

Initial experience of TAS-102 chemotherapy in Australian patients with chemorefractory metastatic colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 71-71
Author(s):  
Azim Jalali ◽  
Hui-Li Wong ◽  
Rachel Wong ◽  
Margaret Lee ◽  
Lucy Gately ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Metastatic Colorectal Cancer ◽  
Real World ◽  
Performance Status ◽  
Progression Free Survival ◽  
Median Number ◽  
Ecog Performance Status ◽  
Number Of Patients

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.

scholarly journals Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Wei Yu ◽  
Qiaomeng Tao ◽  
Yufeng Zhang ◽  
Fengming Yi ◽  
Long Feng
Keyword(s):  
Colorectal Cancer ◽  
Adverse Reactions ◽  
Advanced Colorectal Cancer ◽  
Cox Regression ◽  
Combined Therapy ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Free Survival ◽  
The Third ◽  
Third Line

Background. The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods. We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results. The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment ( p = 0.005 ). Lung metastasis was a negative factor in combined therapy ( p = 0.032 ). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy ( p = 0.034 ). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 ( p = 0.034 ). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions. Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

scholarly journals Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000375 ◽  
Author(s):  
Jean-David Fumet ◽  
Nicolas Isambert ◽  
Alice Hervieu ◽  
Sylvie Zanetta ◽  
Jean-Florian Guion ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Performance Status ◽  
Human Monoclonal Antibody ◽  
Eastern Cooperative Oncology Group ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen

2012 ◽  
Vol 30 (28) ◽  
pp. 3499-3506 ◽  
Author(s):  
Eric Van Cutsem ◽  
Josep Tabernero ◽  
Radek Lakomy ◽  
Hans Prenen ◽  
Jana Prausová ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Survival Times ◽  
Previously Treated

Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. Conclusion Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.

A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer

2009 ◽  
Vol 27 (5) ◽  
pp. 672-680 ◽  
Author(s):  
J. Randolph Hecht ◽  
Edith Mitchell ◽  
Tarek Chidiac ◽  
Carroll Scroggin ◽  
Christopher Hagenstad ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Skin Toxicity ◽  
Adverse Outcomes ◽  
Human Antibody ◽  
Grade 3 ◽  
And Control

Purpose Panitumumab, a fully human antibody targeting the epidermal growth factor receptor, is active in patients with metastatic colorectal cancer (mCRC). This trial evaluated panitumumab added to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment for mCRC. Patients and Methods Patients were randomly assigned within each chemotherapy cohort to bevacizumab and chemotherapy with or without panitumumab 6 mg/kg every 2 weeks. The primary end point was progression-free survival (PFS) within the oxaliplatin cohort. Tumor assessments were performed every 12 weeks and reviewed centrally. Results A total of 823 and 230 patients were randomly assigned to the oxaliplatin and irinotecan cohorts, respectively. Panitumumab was discontinued after a planned interim analysis of 812 oxaliplatin patients showed worse efficacy in the panitumumab arm. In the final analysis, median PFS was 10.0 and 11.4 months for the panitumumab and control arms, respectively (HR, 1.27; 95% CI, 1.06 to 1.52); median survival was 19.4 months and 24.5 months for the panitumumab and control arms, respectively. Grade 3/4 adverse events in the oxaliplatin cohort (panitumumab v control) included skin toxicity (36% v 1%), diarrhea (24% v 13%), infections (19% v 10%), and pulmonary embolism (6% v 4%). Increased toxicity without evidence of improved efficacy was observed in the panitumumab arm of the irinotecan cohort. KRAS analyses showed adverse outcomes for the panitumumab arm in both wild-type and mutant groups. Conclusion The addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy results in increased toxicity and decreased PFS. These combinations are not recommended for the treatment of mCRC in clinical practice.

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