1、Targeted Therapies in Metastatic Colorectal Cancer:An Update ASCO 2022:Targeted Therapies in Metastatic Colorectal Cancer:An Update Bevacizumab is effective in combination with XELOX or FOLFOX-4 Bevacizumab use beyond first progression linked to improvement in survival outcomes Cetuximab in combinat
2、ion with FOLFIRI is an effective first-line therapy Panitumumab is generally well tolerated and has a consistent toxicity profile across studies FOLFIRI=infusional 5-fluorouracil/leucovorin/irinotecan FOLFOX-4=5-fluorouracil/leucovorin/oxaliplatin XELOX=capecitabine/oxaliplatin Bevacizumab is effect
3、ive in combination with XELOX or FOLFOX-4 Bevacizumab(Bev)in combination with XELOX or FOLFOX-4:updated efficacy results from XELOX-1/NO16966,a randomized phase III trial in first-line metastatic colorectal cancer Saltz L,et al.ASCO 2022:Abstract 4028.Background 1.Canadian Cancer Statistics,2022.2.W
4、elch,et al.Cancer Care Ontario,2022.Colorectal cancer is the second leading cause of death from cancer in Canada Approximately 20,800 new cases of colorectal cancer will be diagnosed in 2022 alone1 Monoclonal antibodies(MAbs)such as bevacizumab,cetuximab,and panitumumab in combination with chemother
5、apy drugs are showing considerable promise Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that inhibits the vascular endothelial growth factor(VEGF),secreted by tumour cells to bring about new blood vessel formation Cancer Care Ontario guidelines recommend the addition of bevacizuma
6、b to improve overall survival As first-line therapy in patients with advanced colorectal cancer receiving 5-fluorouracil(5-FU)based chemotherapy As second-line therapy to patients who did not receive bevacizumab as part of their initial treatment2 Background(continued).The NO16966 trial1 was started
7、 as a randomized phase III study to compare the efficacy of XELOX(capecitabine and oxaliplatin)versus FOLFOX-4(5-fluorouracil,leucovorin,and oxaliplatin)The protocol was amended to include bevacizumab in a partially blinded 2 x 2 factorial design to determine the following objectives:Non-inferiority
8、 of XELOX versus FOLFOX-4 Superiority of bevacizumab in combination with chemotherapy(XELOX and FOLFOX-4)versus chemotherapy alone for progression-free survival(PFS)1.Saltz L,et al.ASCO 2022:Abstract 4028.Study design The study was a double-blind study with regard to bevacizumab and placebo administ
9、ration Enrolled patient criteria included:ECOG PS 1 Number of unidentified measurable lesions 1 No prior systemic therapy for advanced metastatic colorectal cancer No prior treatment with oxaliplatin or bevacizumab Patients who had undergone prior adjuvant therapy should not have progressed during o
10、r within 6 months of completion Saltz L,et al.ASCO 2022:Abstract 4028.ECOG=Eastern Cooperative Oncology Group Study design(continued)Saltz L,et al.ASCO 2022:Abstract 4028.FOLFOX-4=5-fluorouraci/leucovorin/oxaliplatin XELOX=capecitabine/oxaliplatin Study design(continued)Patients randomized to XELOX
11、bevacizumab or FOLFOX-4 bevacizumab XELOX+bevacizumab or placebo for 21-day cycle Bevacizumab(or placebo)7.5 mg/kg day 1 Oxaliplatin 130 mg/m2 day 1 Capecitabine 1,000 mg/m2 twice daily days 114 FOLFOX-4+bevacizumab or placebo for 14-day cycle Bevacizumab(or placebo)5 mg/kg day 1 Oxaliplatin 85 mg/m
12、2 day 1 Folinic acid 200 mg/m2 days 1,2 Fluorouracil 400 mg/m2 bolus days 1,2 followed by 600 mg/m2 over 22 h Primary endpoint was progression-free survival Secondary endpoints were overall survival,response rate assessed according to RECIST;safety evaluated using NCI CTC v3.0 Saltz L,et al.ASCO 202
13、2:Abstract 4028.NCI CTC=National Cancer Institute Common Toxicity Criteria RECIST=response evaluation criteria in solid tumours Key findings Significant prolongation of progression-free survival(PFS)in the bevacizumab+oxaliplatinbased chemotherapy arm(HR=0.83 97.5%CI:0.0720.95;p=0.0023)Trend toward
14、prolonged overall survival(OS)Higher proportion of discontinuation of therapy because of adverse effects(AEs)that occurred in the bevacizumab-containing arms versus the placebo-containing arms(31%versus 21%)Most treatment discontinuations,however,due to chemotherapy rather than bevacizumab-related e
15、vents Most common reasons for treatment discontinuation:neurotoxicity,GI events,general disorders,and hematological events Saltz L,et al.ASCO 2022:Abstract 4028.Grade 3 or 4 events with chemotherapy bevacizumab Saltz L,et al.ASCO 2022:Abstract 4028.Key conclusions Significant improvement in progress
16、ion-free survival(PFS)with the addition of bevacizumab to front-line oxaliplatin-based chemotherapy Analysis of on treatment PFS versus general PFS suggests that continuation of bevacizumab until disease progression may be necessary to optimize effect of bevacizumab on PFS Observed overall survival(OS)difference did not reach statistical significance(p=0.077)Saltz L,et al.ASCO 2022:Abstract 4028.Canadian perspective by Dr.Cripps Equivalence of XELOX to FOLFOX-4 and FOLFOX-6 in both first-line an
