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1、ERBITUX every second weekOverview ERBITUX every second week (phase I study)Martinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019. Updated information presented at WCGIC 2008ERBITUX every second week (phase II study)Pfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week r
2、egimenMartinelli E, Macarulla T, Vega-Villegas E, Rodriguez-Braun E, Ciardiello F, Ramos FJ, Rivera F, Stroh C, Nippgen J, Cervantes A, Baselga J, Tabernero J First-line therapy with cetuximab followed by cetuximab plus FOLFIRI in patients with metastatic colorectal cancer: KRAS mutation status corr
3、elates with clinical outcomeMartinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008ERBITUX every second week regimen Study designFOLFIRI added to patients current ERBITUX regimenEvaluate best overall responseProgression-free survival6 weeks treat
4、mentcomplete PK profile obtained during this periodPART IPART II10 endpointDLT assessment20 endpointsMartinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008Group A (control arm)Cohort of 10 patientsERBITUX 400 mg/m2 initial dose then 250 mg/m2 we
5、eklyGroup B (experimental arm)Cohorts of 10 patientsERBITUX at escalating doses for successive cohorts; 400, 500, 600, 700 mg/m2 every 2 weeksERBITUX every second week regimen Patient inclusion criteria18 years of ageHistologically confirmed metastatic colorectal cancer (mCRC) with 1 tumor accessibl
6、e for repeated biopsy1 bi-dimensionally measurable lesion, not in an irradiated areaEGFR-expressing tumor (as detected by IHC)ECOG performance status 2Life expectancy 12 weeksAdequate hematologic, renal, and hepatic functionMartinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated in
7、formation presented at WCGIC 2008ERBITUX every second week regimen Study endpointsPrimary endpointlTo determine the maximum tolerated dose (MTD) of ERBITUX given every 2 weeksSecondary objectives/endpointslSafetylOverall response ratelProgression-free survival (PFS)lPharmacokinetic (PK) parameterslP
8、harmacodynamic (PD), pharmacogenomic, and pharmacogenetic effects lIdentify biomarker profiles that correlate with response or resistanceMartinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008ERBITUX every second week regimen Patient characterist
9、icsaERBITUX q1wERBITUX q2wCharacteristic250 mg/m2(n=13)400 mg/m2(n=13)500 mg/m2(n=14)600 mg/m2(n=12)700 mg/m2(n=10)Total(n=62)Male/female, %46/5469/3179/2175/2540/6063/37Median age, yearsrange65 years, %675575546647775469428071594178256439735065398052ECOG PS, %01254398851509370831708002079165aIntent
10、 to treat (ITT)/safety populationMartinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008Mean (SD) concentrationtime profile at week 5Median ERBITUX trough concentrationsERBITUX every second week regimen PK parametersLogarithmic scaleMartinelli E,
11、 et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008ERBITUX every second week regimen ResponseResponse in Part II of the studyERBITUX q1wERBITUXq2w250 mg/m2 (n=13)400 mg/m2 (n=13)500 mg/m2 (n=14)600 mg/m2 (n=12)700 mg/m2 (n=10)Total(n=62)Partial response,
12、%313957335042Stable disease, %545443503047Overall response rate, % 31 39 57 335042Disease control rate, % 8592100838089Martinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008ERBITUX every second week regimen Progression-free survivalMartinelli E,
13、 et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008ERBITUX q1wERBITUXq2w250 mg/m2 (n=13)400 mg/m2 (n=13)500 mg/m2 (n=14)600 mg/m2 (n=12)700 mg/m2 (n=10)Total(n=62)Patients who had progressed or died, %926929428061Median PFS, months4.47.017.46.96.37.2ERBIT
14、UX every second week regimen Overview of adverse eventsERBITUX q1wERBITUXq2wAdverse events considered ERBITUX related 250 mg/m2 (n=13)400 mg/m2 (n=13)500 mg/m2 (n=14)600 mg/m2 (n=12)700 mg/m2 (n=10)aTotal(n=62)bPart IAny grade, %Grade 3/4, %100010081000920900972Part IIAny grade, %Grade 3/4, %1002385
15、0865083889448925Martinelli E, et al. Ann Oncol 2008;19 (Suppl. 6):Abstract PD-019.Updated information presented at WCGIC 2008There were no deaths due to cetuximab-related adverse events in either part of the studyan=9 in Part II; bn=61 in Part IIERBITUX every second week regimenBiweekly cetuximab an
16、d irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracilPfeiffer P, Nielsen D, Bjerregaard JK, Qvortrup C, Yilmaz M, Jensen BV Pfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week regimen Treatment p
17、lanEligible patients treated with one of two ERBITUX + irinotecan regimens according to dateDisease progression or unacceptable toxicityNovember 2005December 2006Biweekly ERBITUX regimen:2ERBITUX (500 mg/m2 every second week from week 1)a plus irinotecan 180 mg/m2 every second weekJanuary 2005Septem
18、ber 2005Weekly ERBITUX regimen:1ERBITUX (400 mg/m2 initial dose then 250 mg/m2 weekly) plus irinotecan 180 mg/m2 every second week1Pfeiffer P, et al. Acta Oncol 2007;46:697701. 2Pfeiffer P, et al. Ann Oncol 2008;19:11411145.aInitially patients received ERBITUX weekly (for 6 standard doses) then biwe
19、ekly if no evidence of progressive disease. This was phased out after 3 months and the biweekly dose of 500 mg/m2 was given from week 1.ERBITUX every second week regimen Patient inclusion criteriaHistologically proven colorectal adenocarcinomaNon-resectable diseaseDisease progression after prior tre
20、atment with 5-FU, irinotecan and oxaliplatinEGFR expression was not determinedPfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week regimen Patient characteristicsPatient characteristicsWeekly ERBITUX +irinotecan(n=65)Biweekly ERBITUX + irinotecan(n=74)Inclusion periodJanSep 2005No
21、v 2005Dec 2006Median age, years range57 29-7763 23-78Gender, M / F, %62/3862/38ECOG performance status (PS), %:01238218928Prior therapy, %:OxaliplatinIrinotecan10010095100Primary tumor site, colon/rectum, %63/3774/26Pfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week regimenRespo
22、nseEfficacyWeekly ERBITUX+ irinotecan(n=65)Biweekly ERBITUX + irinotecan (n=74)Complete response (CR), %01Partial response (PR), %1924Stable disease (SD), %4752 Objective response rate (CR+PR), %1926Disease control rate (CR+PR+SD), %6677Pfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every sec
23、ond week regimenProgression-free survival (PFS)mPFS ERBITUX weekly regimen: 5.4 monthsmPFS ERBITUX bi-weekly regimen: 5.4 monthsPfeiffer P, et al. Ann Oncol 2008;19:11411145.100%75%50%25%0% without PD03912Time (months)ERBITUX weekly regimen (n=65)ERBITUX bi-weekly regimen (n=74)6ERBITUX every second
24、 week regimenOverall survival (OS)Pfeiffer P, et al. Ann Oncol 2008;19:11411145.mOS ERBITUX weekly regimen: 10.4 monthsmOS ERBITUX bi-weekly regimen: 8.9 months100%75%50%25%0%Probability of survival03912Time (months)ERBITUX weekly regimen (n=65)ERBITUX bi-weekly regimen (n=74)6ERBITUX every second w
25、eek regimenRelating outcome to skin toxicityOutcomeSkin toxicity (n=63)No skin toxicity (n=11)p-valueMedian PFS, months6.23.40.004Median OS, months9.96.30.004ERBITUX every second week regimenPfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week regimen Most common grade 3/4 adverse
26、 eventsGrade 3/4 adverse events, %Weekly ERBITUX + irinotecan(n=65)Biweekly ERBITUX + irinotecan % (n=74) Diarrhea109Skin85Fatigue84Neutropenia47Nail33Anaphylactic reaction51Nausea30Vomiting30Pfeiffer P, et al. Ann Oncol 2008;19:11411145.ERBITUX every second week regimen ConclusionsBiweekly ERBITUX
27、plus irinotecan resulted in similar response rates, PFS, and OS as those reported in the historical control group of patients who received irinotecan plus standard weekly ERBITUXAdministering ERBITUX in an every second week regimen does not appear to increase the frequency or severity of adverse eve
28、nts, including allergic reactionsERBITUX every second week plus irinotecan is a convenient, effective and well tolerated regimen for heavily pre-treated patients with advanced CRCAn ongoing Danish phase II study is investigating this regimen further in a larger patient populationPfeiffer P, et al. Ann Oncol 2008;19:11411145.
