- Email: [email protected]
P-964 What do we know about dosing Tarceva™ based on erlotinib pharmacokinetics in cancer patients?
Posters I Targeted therapies -H- VS 35% ++) and p A K T (90%-H- VS 50% +) after 15 days of treatment. Nine patients with stable disease (SD) reported a variable pattern of marker expression changes, whereas 18. pat]ants with progression disease (PD) reported a t]'end to enhancement of E G F R ~ 0 e 30%+ vs ,50%H~). p-MAPK (50%++ vs 70% ',~H~) and p-AKT (10%+ vs 30%+) expression In addit]on, we evaluated the association between the status of EGFRs). p~MAPK and p-AKT be~re t]'eatment and the response to gefit]nib p-AKT overexpression (++/+ H ) was observed in 100% of pat]ants with part]al response, in 4,5% of patients with stable disease and in 15% of pat]ants w~th progression disease; E G F R p overexpress~on was observed in 50% of pat]ants with PR. in 25% of patients with SD and in 6% of pat]ants with PD. On the contrary, dinical response to gofltinib cld not differ according to baseline !~MAPK status. Skin rash or gastTo intust]nal toxicity was observed in 75%. 50% and 23% of the pat]ants with PR. SD or PD. resgect]vely: Conclusions: We suggest a potont]al role of different signal transduction protein expression in bucoal mucose as possible markers of "in vivo" act]vity of targeted therapies, such as ger~nib Pat]ants accrual into this study is continLing Correlation between tumor tissue and buccal mucosa protein expression is ongoing, as well as studies of EGFR mutations, amplification and polym orphisms
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EKB-569: An Irreversible EGFR b/rosins klnass inhibitor
K Matsui ~. S Negoro ~. S Kudch 3. K Nakagawa ~. T Hirashima ~. K. Takoda ~. N. Yoshimura ~. M. Fukuoka ~ . ~Osaka Pretectura/Medical Center for Resptratory and A#erg/c Dtseases, Department ot Thotas~c Malignancy,
Hat~k~no, Japan: 2Dept of Medical Ontology Osaka CRy Hospital, Osaka, Japan, 3First Internal Msclicina Osaka City University of Medcina, Osaka, Japan: ~Dept of MeeJcal Onset tOnk~ Umverstt~, Osaka~ayama, Japan Background: Epidermal growth factor recaptor (EGFR. HER 1) pathway is an important therageut]c target because the maJonty of epithelial cancers, such as the lung. breast, and stomach, over express this recaptor. IJgend binding to EGFR induce the format]on of hom~dimers and hetere~:limers with ether EGFR family members (PIER 2. HER 3. and HER 4). which leads to activation of the receptor tyro=no kinaso, autophosphorylat]on and subsequently tumor cell growth, proliferation and motastas~s. Last year. Tarceva was approved by FDA for non-small cell lung cancer following Gefit]nib Both drug inhibit only EGFR-related tyrusine Idnase However. dual inhibitors or pan4-1ER inhibltors, which ichiblt two or more HER tyrusine kinases, may be more eff~ct]ve as it is Imown that hetere-dimers make tumors more aggressive than homo-dimers Moreover. irreversible inhibltors of HER tyresine Idnases may be more effective to prolong target suppression EKB-56g is an orally eo~ve, low molecularweight, selective, irreversible inhibitor of EGFR. EKB 569 inhibits EGFR tyres~ne I~nase actrv~y more than HER 2 tyrusino I~nase activity; the IC 50 for EGFR is about 30 times lower than that for HER 2. In the US. Phase I study was conducted by two dosage schedules, intermittent dosage and cont]nuous dosage schedule. EKB 569 was generally well tolerated in advanced solid tumor pat]ants. DLT was diarrhea and MTD was 75mg/day for both dosage schedules. Phase Ltll studies combined with chemotherapy have been initiated Method,=: In Japan. Phase I study for advanced solid tumor patients was conducted Result.=: ] h e results of clinical tTials of EKB-56g will be presented in detail
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phase II study evaluating the dlnlcel efficacy of TG4010 (IVIVA-MUCI-IL2) In association wlth dsplatin and vlnorslblne In patients with non small cell lung cancer
B Menneoiar ~. R Ramlsu 2. J Rolski 3. H Lena 4. M Plass 5. E: Levy 6. M. Krzakowsl~ 7, D. Hess u, J. Limache~. T. Volu 1° . lHOpttaux Un/versrta/res,
Strasbourg, Franoa: 2 Wtalkopofsloe Centrum, Poznan, Poland. 3 Centtum Onkologttqnstytut, Krak~/v, Poland. ~H~p/tal de Pontchatllou, Rennes, France. ~Kantonsspfal, Basal, Swt~zarland, eHSpital Europden Gaorges Pompidou, Pans, France, 7 The Maria Sktodowska~:,une Cancer Centre, Warszawa, Po/and, 6 Kantonssp/tal, St Gallon, Sv,ctzerland. g Transgene SA, Sttasbourg, France, ~; Acadamic Erasme Hospttal, Brussals, Belgium Background: TG4010 is a recombinant viral vector expressing both IL2 and the tumor-associated ant]gen MUC1 This vector is based on the Modified 'v3rus Ankara (MVA). a vaccmia virus strain significantly attenuated We present here interim results of a phase II study in which TG4010 was assessed alone or in combination with cisplatin and vinorelbine in advanced NSCLC patients Methods: A mult]-center randomiTed, two stage Simon design, two arm. phase II study in stage IIIB/IV. PS 0-1. NSCLC patients was conducted. Arm 1 : TG4010 was combined upfrent with cieplatin (100 mg/m 2 J1) and vinorelbine (25 mg/m 2 J 1&J6). Arm 2: patients wore b-eared wtth TG4010 alone, followed by TG4Ol0 + clsplabn and vinorelbino upon disease progression. Responses rate were evaluated acoording to RECIST and validated by an independent
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central review. Median time to progression (TIP) and median overall survival (OS) were est]matod according to the method of KaplanMeler Results: 65 patients (1,5 stage IIIb. 50 stage IV) have been enrolled In arm 1. a partial response (PR) was observed in 13/3,5 pat]ants (37%) Disease control at 12 weeks was observed in 24/3,5 patients (68.%) In arm 2. two pat]ants experienced a stable disease for more than six months with TG4010 alone (up to 211 days), and. in the subsequent combinat]on with chemotherapy, a PR was observed in 3 out of 14 pat]ants Arm 2 did not meet the criteria Ibr moving forward to second stage. ] h e median ~ Ibr arm 1 was 6.1 [4.1 ;6.7] months. The intent to treat median OS for the whole study population is presently 14.9 [11.9;23.4] months with a 12 month ost]matecl survival rate of 61%. RR. TTP and OS correlate with the presence o f a MUC1 specific cellular immune response. TG4010 is well tolerated, injection s~te reaction being the must frocFJont study drug related adverse event. Conclusions: The combination of TG4010 with standard chemotherapy shows encouraging results just]lying additional studies
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What do we Imow about dosing Tarceva TM based on srlotlnlb pharmacoklnstlce In cancer patients?
J Wolf ~ . J Lu2. ~. Lurn 2. D Zborowski I . A Rakhlt ~. G Clark 1. M Ptaszynsld I . M Hamilton ~ ~OSIPharmacaut.icals,/nc, Boulder, Color-ado,
USA, 2 Genentech Inc., South San Francisco, CA, USA, 3/~ Hottman LaRoche, Nut/ey, NJ, USA Background: Edot]nib hydrochloride (edotinib. Tarceva TM . OS1-774) is an orally active, potent and seleotlvo inhibitor of the epidermal growth factor receptor (LGFR) tyrosme kinase, it is indicated for the treatment of patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one pnor chemotherapy regimen. Statistical analyses were conducted on data from a number of clinical stuclas wlth Tarcova TM to determine if patient charactenst]us such as sex; smoking status; conoomltant use of opioids/Ipporamide or calcium channel blockers might suggest differential dosing of ertot]nib Pret]'eatment of healthy subjects with a CYP3A4 inducer. dfampicin, prior to a single dose of edot]nib resulted in a 66% decrease in p~asma AUC. therefore this covariate was also examined in the analysis of pat]ant data Results of populat]on PK modeling were examined for other significant covariates that could not be analyzed on a study~y-study basis Methods: Data from 2 Phase I. 5 Phase II (ovanan. head and neck. NSCLC. breast, and aerodigust]ve cancers) and 3 Phase III (NSCLC) erlotinib stucles were included in those analyses. Two of the Phase III studus evaluated odot]nib in combination with chsmctheragy, all others used monothorapy. Statistical methods employed included Analysis of Varlanoe. Analysis of Covarlanco. Spearman Rank Correlation Analysis and Student's t tests. Edot]nib expusure was evaluated in terms of AUC0 24n. Cmax and C24n derived drectly by nencompartmental analysis for some studies and as post~oc ust]matos from Population PK analyses in others. P~alues <0.05 wore considered statistically significant Results: In all studies where both male and ~male pat]ants were treated. there was atTend towards greater exposure to ertot]nib in ~male as compared with male pat]ants "Iris reached significance in only one study (Phase I) ~3r stascly state Crnax (p O 03,55). but not for C2,~ or ,&,UCQ_24~ ~ a 49% increase in steady state Cr~ax observed ~ r females compared with male pat]ants Where data ware available for smoldng status (1 Phase III study. n = 342). all three measures of exposure were significantly decreased in current smokers. The greatest impact was a 70% decrease in C24n in current vs. never/former smokers. No clinically relevant correlations of edctinib AUC0 24. Cr~ax. or C24n with concomitant use of oplords/Iogeramide, calcium channel blockers or presence of liver metastases wore observed. Although the co admirlstratlon of CYP3A4 inducers was not identtfied in the population PK models as a s~gnificant covanato, these analyses wore limited beth by the small number of pat]ents taking such inducers and by the lack of data concerning the dose or durat]on over wftch such drugs were administered Conclusions: The data from these analyses suggest that there is no evidence to support dose adjustment of Tarcova TM in cancer pat]ants based on sex: use of opioldsllopersmido or calcium channel blockers: or the presence of liver metastases Dose adjustment may be considered to compensate for faster dearanea of edotinib in smokers and in patients taldng CYP3A4 inducers Studus are ongoing to confirm this observation.
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EKB-569: An Irreversible EGFR b/rosins klnass inhibitor
K Matsui ~. S Negoro ~. S Kudch 3. K Nakagawa ~. T Hirashima ~. K. Takoda ~. N. Yoshimura ~. M. Fukuoka ~ . ~Osaka Pretectura/Medical Center for Resptratory and A#erg/c Dtseases, Department ot Thotas~c Malignancy,
Hat~k~no, Japan: 2Dept of Medical Ontology Osaka CRy Hospital, Osaka, Japan, 3First Internal Msclicina Osaka City University of Medcina, Osaka, Japan: ~Dept of MeeJcal Onset tOnk~ Umverstt~, Osaka~ayama, Japan Background: Epidermal growth factor recaptor (EGFR. HER 1) pathway is an important therageut]c target because the maJonty of epithelial cancers, such as the lung. breast, and stomach, over express this recaptor. IJgend binding to EGFR induce the format]on of hom~dimers and hetere~:limers with ether EGFR family members (PIER 2. HER 3. and HER 4). which leads to activation of the receptor tyro=no kinaso, autophosphorylat]on and subsequently tumor cell growth, proliferation and motastas~s. Last year. Tarceva was approved by FDA for non-small cell lung cancer following Gefit]nib Both drug inhibit only EGFR-related tyrusine Idnase However. dual inhibitors or pan4-1ER inhibltors, which ichiblt two or more HER tyrusine kinases, may be more eff~ct]ve as it is Imown that hetere-dimers make tumors more aggressive than homo-dimers Moreover. irreversible inhibltors of HER tyresine Idnases may be more effective to prolong target suppression EKB-56g is an orally eo~ve, low molecularweight, selective, irreversible inhibitor of EGFR. EKB 569 inhibits EGFR tyres~ne I~nase actrv~y more than HER 2 tyrusino I~nase activity; the IC 50 for EGFR is about 30 times lower than that for HER 2. In the US. Phase I study was conducted by two dosage schedules, intermittent dosage and cont]nuous dosage schedule. EKB 569 was generally well tolerated in advanced solid tumor pat]ants. DLT was diarrhea and MTD was 75mg/day for both dosage schedules. Phase Ltll studies combined with chemotherapy have been initiated Method,=: In Japan. Phase I study for advanced solid tumor patients was conducted Result.=: ] h e results of clinical tTials of EKB-56g will be presented in detail
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phase II study evaluating the dlnlcel efficacy of TG4010 (IVIVA-MUCI-IL2) In association wlth dsplatin and vlnorslblne In patients with non small cell lung cancer
B Menneoiar ~. R Ramlsu 2. J Rolski 3. H Lena 4. M Plass 5. E: Levy 6. M. Krzakowsl~ 7, D. Hess u, J. Limache~. T. Volu 1° . lHOpttaux Un/versrta/res,
Strasbourg, Franoa: 2 Wtalkopofsloe Centrum, Poznan, Poland. 3 Centtum Onkologttqnstytut, Krak~/v, Poland. ~H~p/tal de Pontchatllou, Rennes, France. ~Kantonsspfal, Basal, Swt~zarland, eHSpital Europden Gaorges Pompidou, Pans, France, 7 The Maria Sktodowska~:,une Cancer Centre, Warszawa, Po/and, 6 Kantonssp/tal, St Gallon, Sv,ctzerland. g Transgene SA, Sttasbourg, France, ~; Acadamic Erasme Hospttal, Brussals, Belgium Background: TG4010 is a recombinant viral vector expressing both IL2 and the tumor-associated ant]gen MUC1 This vector is based on the Modified 'v3rus Ankara (MVA). a vaccmia virus strain significantly attenuated We present here interim results of a phase II study in which TG4010 was assessed alone or in combination with cisplatin and vinorelbine in advanced NSCLC patients Methods: A mult]-center randomiTed, two stage Simon design, two arm. phase II study in stage IIIB/IV. PS 0-1. NSCLC patients was conducted. Arm 1 : TG4010 was combined upfrent with cieplatin (100 mg/m 2 J1) and vinorelbine (25 mg/m 2 J 1&J6). Arm 2: patients wore b-eared wtth TG4010 alone, followed by TG4Ol0 + clsplabn and vinorelbino upon disease progression. Responses rate were evaluated acoording to RECIST and validated by an independent
$373
central review. Median time to progression (TIP) and median overall survival (OS) were est]matod according to the method of KaplanMeler Results: 65 patients (1,5 stage IIIb. 50 stage IV) have been enrolled In arm 1. a partial response (PR) was observed in 13/3,5 pat]ants (37%) Disease control at 12 weeks was observed in 24/3,5 patients (68.%) In arm 2. two pat]ants experienced a stable disease for more than six months with TG4010 alone (up to 211 days), and. in the subsequent combinat]on with chemotherapy, a PR was observed in 3 out of 14 pat]ants Arm 2 did not meet the criteria Ibr moving forward to second stage. ] h e median ~ Ibr arm 1 was 6.1 [4.1 ;6.7] months. The intent to treat median OS for the whole study population is presently 14.9 [11.9;23.4] months with a 12 month ost]matecl survival rate of 61%. RR. TTP and OS correlate with the presence o f a MUC1 specific cellular immune response. TG4010 is well tolerated, injection s~te reaction being the must frocFJont study drug related adverse event. Conclusions: The combination of TG4010 with standard chemotherapy shows encouraging results just]lying additional studies
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What do we Imow about dosing Tarceva TM based on srlotlnlb pharmacoklnstlce In cancer patients?
J Wolf ~ . J Lu2. ~. Lurn 2. D Zborowski I . A Rakhlt ~. G Clark 1. M Ptaszynsld I . M Hamilton ~ ~OSIPharmacaut.icals,/nc, Boulder, Color-ado,
USA, 2 Genentech Inc., South San Francisco, CA, USA, 3/~ Hottman LaRoche, Nut/ey, NJ, USA Background: Edot]nib hydrochloride (edotinib. Tarceva TM . OS1-774) is an orally active, potent and seleotlvo inhibitor of the epidermal growth factor receptor (LGFR) tyrosme kinase, it is indicated for the treatment of patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one pnor chemotherapy regimen. Statistical analyses were conducted on data from a number of clinical stuclas wlth Tarcova TM to determine if patient charactenst]us such as sex; smoking status; conoomltant use of opioids/Ipporamide or calcium channel blockers might suggest differential dosing of ertot]nib Pret]'eatment of healthy subjects with a CYP3A4 inducer. dfampicin, prior to a single dose of edot]nib resulted in a 66% decrease in p~asma AUC. therefore this covariate was also examined in the analysis of pat]ant data Results of populat]on PK modeling were examined for other significant covariates that could not be analyzed on a study~y-study basis Methods: Data from 2 Phase I. 5 Phase II (ovanan. head and neck. NSCLC. breast, and aerodigust]ve cancers) and 3 Phase III (NSCLC) erlotinib stucles were included in those analyses. Two of the Phase III studus evaluated odot]nib in combination with chsmctheragy, all others used monothorapy. Statistical methods employed included Analysis of Varlanoe. Analysis of Covarlanco. Spearman Rank Correlation Analysis and Student's t tests. Edot]nib expusure was evaluated in terms of AUC0 24n. Cmax and C24n derived drectly by nencompartmental analysis for some studies and as post~oc ust]matos from Population PK analyses in others. P~alues <0.05 wore considered statistically significant Results: In all studies where both male and ~male pat]ants were treated. there was atTend towards greater exposure to ertot]nib in ~male as compared with male pat]ants "Iris reached significance in only one study (Phase I) ~3r stascly state Crnax (p O 03,55). but not for C2,~ or ,&,UCQ_24~ ~ a 49% increase in steady state Cr~ax observed ~ r females compared with male pat]ants Where data ware available for smoldng status (1 Phase III study. n = 342). all three measures of exposure were significantly decreased in current smokers. The greatest impact was a 70% decrease in C24n in current vs. never/former smokers. No clinically relevant correlations of edctinib AUC0 24. Cr~ax. or C24n with concomitant use of oplords/Iogeramide, calcium channel blockers or presence of liver metastases wore observed. Although the co admirlstratlon of CYP3A4 inducers was not identtfied in the population PK models as a s~gnificant covanato, these analyses wore limited beth by the small number of pat]ents taking such inducers and by the lack of data concerning the dose or durat]on over wftch such drugs were administered Conclusions: The data from these analyses suggest that there is no evidence to support dose adjustment of Tarcova TM in cancer pat]ants based on sex: use of opioldsllopersmido or calcium channel blockers: or the presence of liver metastases Dose adjustment may be considered to compensate for faster dearanea of edotinib in smokers and in patients taldng CYP3A4 inducers Studus are ongoing to confirm this observation.