Conference Proceedings for Hematology/ Oncology Pharmacists, Physician

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Indiana University Hospital Indianapolis, IN R. Donald HarGeJ, PharmD, FCCP, BCPS, BCOP Assistant Pro8essor o8 Hematology/Medical Oncology Director, Phase I Program Emory University School o8 Medicine Winship Cancer Institute Atlanta, GA Kr:st:n Hennen7ent, PharmD, MBA, BCPS Medical Writer Syntaxx Communications, Inc. Duluth, GA L:sa Holle, PharmD, BCOP Medical Writer Syntaxx Communications, Inc. Duluth, GA Laura Jung, PharmD Medical Writer Syntaxx Communications, Inc. Duluth, GA Faculty diScloSurES Chr:s Fausel is a consultant =or Amgen, Inc and Abraxis BioScience, Inc. Laura Jung has an immediate =amily member who is on a speaker 9s bureau =or P zer, Inc. Kr:st:n Hennen7ent, L:sa Holle, and Laura Jung are employees o= Syntaxx Communications, Inc. Donald HarGeJ has nothing to disclose. additional diScloSurES The opinions expressed in this report are those o= the =aculty and reviewers and do not represent an endorsement by Syntaxx Communications or the companies providing educational grant support o= any speci c therapeutics or approaches to diagnosis or patient management. Syntaxx Communications assumes no responsibility =or errors or omissions in this document. The reader is advised to check the appropriate medical literature and the product in=ormation currently provided by the manu=acturer o= each drug to be administered and/or contact the manu=acturer directly to veri=y the dosage, the method and duration o= administration, or contraindications. It is the responsibility o= the healthcare pro=essional, relying on independent experience and knowledge o= patients, to determine the best treatment =or a patient. This report contains discussion o= unpublished and/or investigational uses o= agents that are not approved by the US Food and Drug Administration. Syntaxx Communications and Amgen, Genentech, and sano 3aventis do not recommend the use o= any agent outside o= its labeled indication. Con7erence Proceed:ngs: General in7ormat:on 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 3 SyNOPSiS These con=erence proceedings o= the 2008 American Society o= Clinical Oncology Annual Meeting (held May 30-June 3, 2008 at McCormick Place in Chicago, IL) contain a collection o= abstract summaries, written by clinical oncology pharmacists who attended the meeting. This report represents selected plat=orm or poster presentations that describe current, cutting 3edge, original work that are likely to result in a change in practice patterns or techniques used by pharmacists, physician assistants, and/or advanced practice nurse practitioners. EDUCATiONAL OBJECTivE The purpose o= the proceedings is to provide the latest and particularly relevant in=ormation and study results presented during the 2008 ASCO Annual Meeting to pharmacists, physician assistants, and advanced practice nurse practitioners who specialize in hematology/oncology. Conference Prodeedings of the Hematology/Oncology Pharmacists, Physician Assistants, and Nurse Practitioners: 2008 American Society of Clinical Oncology (ASCO) Annual Meeting 4 2 Faculty, diScloSurES, and GEnEral inFormation 3 SynopSiS and Educational objEctivE 4 tablE oF contEntS 6 brEaSt cancEr 6 Poole CJ, et al. tAnGO: a randomized phase III trial o= gemicitabine (gem) in paclitaxel 3containing, epirubicin/cyclophosphamide 3based, adjuvant chemotherapy (CT) =or women with early stage breast cancer (EBC). Abstract 506. 8 Muss HB, et al. Standard chemotherapy (CMF or AC) versus capecitabine in early 3stage breast cancer (BC) patients aged 65 and older: results o= CALGB/CTSU 49907. Abstract 507. 10 Miles D, et al. Randomized, double 3blind, placebo 3 controlled phase III study o= bevacizumab (B) with docetaxel (D) or docetaxel with placebo (PL) as rst 3line therapy =or patients with locally recurrent or metastatic breast cancer (mBC): AVADO. Abstract LBA1011. 12 Gnant M, et al. Adjuvant ovarian suppression combined with tamoxi=en or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine 3responsive, stage I and II breast cancer: rst e= cacy results =rom ABCSG 312. Abstract LBA4. 16 O 9Shaughnessy J, et al. A randomized study o= lapatinib alone or in combination with trastuzumab in heavily pretreated HER 32+ metastatic breast cancer progressing on trastuzumab therapy. Abstract 1015. 18 colorEctal cancEr 18 Van Cutsem E, et al. KRAS status and e= cacy in the rst 3line treatment o= patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. Abstract 2. 21 Sargent DJ, et al. Con rmation o= de cient mismatch repair (dMMR) as a predictive marker =or lack o= bene t =rom 5 3FU based chemotherapy in stage II and III colon cancer (CC): a pooled molecular reanalysis o= randomized chemotherapy trials. Abstract 4008. 24 Nikcevich DA, et al. E==ect o= intravenous calcium and magnesium (IV CaMg) on oxaliplatin 3induced sensory neurotoxicity (sNT) in adjuvant colon cancer: results o= the phase III placebo 3controlled, double 3blind NCCTG trial N04C7. Abstract 4009. 26 Punt CJ, et al. Randomized phase III study o= capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study o= the Dutch Colorectal Cancer Group (DCCG). Abstract LBA4011. 28 lunG cancEr 28 Pirker R, et al. FLEX: A randomized, multicenter, phase III study o= cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the rst 3line treatment o= patients with advanced non 3 small cell lung cancer (NSCLC). Abstract 1. 30 Ciuleanu TE, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study. Abstract 8011. 31 Berghmans T, et al. =or the European Lung Cancer Working Party. A phase III randomized study comparing concomitant standard cisplatin (P) 3 etoposide (E) and chest irradiation to concomitant etoposide plus daily cisplatin and chest irradiation as induction therapy =or limited (LD) small 3cell lung cancer (SCLC). Abstract 7521. 33 Natale RB, et al. S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/ cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E 3SCLC). Abstract 7512. 35 Soon Y, et al. Duration o= chemotherapy =or advanced non 3small cell lung cancer: An updated systematic review and meta 3analysis. Abstract 8013. 38 Patel JD, et al. Pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as rst 3line therapy =or advanced non 3squamous non 3small cell lung cancer (NSCLC). Abstract 8044. 40 Heigener DF, et al. =or the ABC Study Group. Topotecan/cisplatin (TP) compared to cisplatin/ etoposide (PE) =or patients with extensive disease 3 small cell lung cancer (ED 3 SCLC): Final results o= a randomised phase III trial. Abstract 7513. 42 Le Chevalier T, et al. =or the IALT Collaborative Group. Long 3term results o= the International Adjuvant Lung Cancer Trial (IALT) evaluating adjuvant cisplatin 3based chemotherapy in resected non 3small cell lung cancer (NSCLC). Abstract 7507. 43 Kiura K, et al =or the Okayama Lung Cancer Study Group (OLCSG). Randomized phase III trial o= docetaxel and cisplatin combination chemotherapy versus mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiation therapy =or locally advanced non 3small 3cell lung cancer: OLCSG 0007. Abstract 7515. 45 SupportivE carE 45 Thromboembol:sm 45 Cancer and Thrombosis I: The Risk o= Venous Thromboembolism in Patients with Cancer. Categorical Course. Chair: Gary H. Lyman MD, MPH, FRCP Khorana AA. Risk =actors, biomarkers and a risk model =or cancer 3associated thrombosis. Con7erence Proceed:ngs: Table o7 Contents 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 5 46 Cancer and Thrombosis II: The Prevention o= Venous Thromboembolism in Patients with Cancer. Categorical Course. Chair: Gary H. Lyman MD, MPH, FRCP Kakkar AK. Prevention o= venous thromboembolism in the cancer surgical patient. 47 Levine MN. Prevention o= venous thrombosis in ambulatory cancer patients receiving chemotherapy. 48 Cancer and Thrombosis III: The Role o= Anticoagulation in the Treatment o= Patients with Cancer. Categorical Course. Chair: Gary H. Lyman MD, MPH, FRCP Strei== MB. Diagnosis and initial management o= venous thromboembolism in cancer patients. 48 Lee A. The role o= anticoagulation. Long 3term treatments and special populations. 49 Lyman GH. Conclusions and summary o= the ASCO VTE guidelines. 50 Anem:a 50 Erythropoiesis 3Stimulating Agents in Cancer Chemotherapy: Recent Developments and Clinical Implications. Chair: J. Douglas Rizzo, MD, Rizzo JD. ASH 3ASCO erythropoiesis 3stimulating agents guideline update: evidence base and recommendations. 51 Silver S. Erythropoiesis 3stimulating agents: the regulatory environment. 52 Thompson K. Erythropoiesis 3stimulating agents: adapting clinical practice to evolving evidence and policy. 53 Ra=topoulos H, et al. Assessing risks and bene ts o= erythropoiesis 3 stimulating agents by tumor type in advanced solid tumor patients: a meta 3analysis o= 17 randomized controlled trials including 4,646 patients. Abstract 9541. 55 Fat:gue 55 Morrow GR, et al. A phase III randomized, placebo 3 controlled, double 3blind trial o= a eugeroic agent in 642 cancer patients reporting =atigue during chemotherapy: A URCC CCOP study. Abstract 9512. 56 Neutropen:a 56 Knop= KB, et al. Impact o= neutropenia on chemotherapy administration in elderly patients with advanced non 3small cell lung cancer (NSCLC). Abstract 9624. 57 Wound Heal:ng 57 Sugrue MM, et al. Serious wound healing complications (sWHC) =ollowing surgery in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab (BV): Results =rom the BRiTE observational cohort study (OCS). Abstract 4105. 59 Bone Health 59 Shapiro CL, et al. E==ect o= zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian =ailure (OF) due to adjuvant chemotherapy (AdC): rst results =rom CALGB trial 79809. Abstract 512. 61 Gralow JR, et al. E==ects o= denosumab on bone resorption in patients with solid tumors and bone metastases: comparison o= serum 3C telopeptide levels =rom two randomized, active 3controlled, phase II trials. Abstract 9574. 63 Hines SL, et al. N02C1: a phase III randomized, placebo controlled, double blind trial o= risedronate =or prevention o= bone loss in premenopausal women undergoing adjuvant chemotherapy =or breast cancer (BC). Abstract 525. 64 Ellis GK, et al. Subgroup analysis o= a randomized phase III study o= the e==ect o= denosumab in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy. Abstract 546. 67 Coleman RE; on behal= o= the ATAC Trialists 9 Group. Long 3term e==ects o= anastrozole on bone mineral density: seven 3year results =rom the ATAC trial. Abstract 587. 69 Card:ac Health 69 Morris PG, et al. Dose 3dense (dd) doxorubicin 3 cyclophosphamide (AC) x 4 and short 3term changes in le=t ventricular ejection =raction (LVEF) alone or with bevacizumab (B) in patients (pts) with early stage breast cancer (BC). Abstract 637. 70 General Health 70 Goodwin PJ. Frequency o= vitamin D (vit D) de ciency at breast cancer (BC) diagnosis and association with risk o= distant recurrence and death in a prospective cohort study o= T1 33, N0 31, M0 BC. Abstract 511. 72 Alibhai SM, et al. Impact o= androgen deprivation therapy (ADT) on bone, cardiovascular, and endocrine outcomes: a propensity 3matched analysis o= 20,000 patients. Abstract 5012. 74 proGram Evaluation Form 6 " Toxicity, dose intensity, and tolerability " Serious adverse events (AEs) baSElinE charactEriSticS Characteristic % o8 Patients a EC 3T (n=1,571) EC 3GT (n=1,570) EcoG IeK?HKF:G<e sM:MNs 0 1 2 93 6 1 91 8 1 meGHI:Ns:E sM:MNs pKeFeGHI:Ns:E peKBFeGHI:Ns:E pHsMFeGHI:Ns:E bBE:MeK:E HHIAHKe<MHFR hRsMeKe<MHFR uGDGHPG 45 8 35 1 7 4 46 7 36 1 5 5 de GBMBOe SNKgeKR m:sMe<MHFR bKe:sM <HGseKO:MBHG 56 44 56 44 me=B:G MBFe ?KHF sNKgeKR MH eGMKR, = (K:Gge) 32 (25 341) 31 (24 340) dBsM:G<e MH <EHseM K:=B:E F:KgBG < 1 FF 1 MH < 5 FF 5 MH < 10 FF e 10 FF 9 28 21 42 10 28 22 40 tNFHK =B:FeMeK t1 t2 t3 38 54 8 36 55 9 pgr sM:MNs neg:MBOe we:DER IHsBMBOe pHsBMBOe uGDGHPG 37 8 25 30 37 8 27 28 tNFHK MRIe dN<M:E /BG sBMN lH;NE:K tN;NE:K/<KBxMB?HKF mN<BGHNs me=NEE:KR oMAeK 89 13 2 1 1 4 88 13 2 1 1 4 tNFHK gK:=e 1 2 3 4 30 66 4 30 66 v:s<NE:K ERFIA:MB< BGO:sBHG 59 58 backGround Gemcitabine combined with paclitaxel improves time to progression and overall survival (OS) in women with metastatic breast cancer. 1 A previous Cancer and Leukemia Group B study (CALGB 9344) demonstrated a bene t o= sequential adjuvant chemotherapy with doxorubicin and cyclophosphamide =ollowed by paclitaxel. 2 StudJ Object:Ge : compare e= cacy o= sequential adjuvant chemotherapy regimen o= epirubicin and cyclophosphamide, =ollowed by paclitaxel and gemcitabine (EC-GT) with epirubicin and cyclophosphamide, =ollowed by paclitaxel alone (EC-T). Study dESiGn International, multicenter, randomized, controlled, phase 3 trial (tAnGO) El:g:b:l:tJ " Operable breast cancer " Clear resection margins " Any axillary lymph node status " Any hormone receptor status: original eligibility was poor hormone receptor status, but changed when results =rom another study became available Pr:marJ endpo:nt : 5 3year disease 3=ree survival (DFS) SecondarJ endpo:ntss SecondarJ endpo:nts " 5 3 and 10 3year OS " 10 3year DFS Con7erence Proceed:ngs: Breast Cancer brEaSt cancEr SESSionS Poole CJ, H:ller L, Howard HC, et al. tAnGO: a random:zed phase iii tr:al o7 gem:c:tab:ne (gem) :n pacl:taxel 3conta:n:ng, ep:rub:c:n/cJclophospham:de 3based, adjuGant chemotherapJ (CT) 7or women w:th earlJ stage breast cancer (EBC). J Clin Oncol . 2008;26(suppl pt 1):8s. Abstract 506. Epirubicin 90 mg/m 2 + cyclophosphamide 600 mg/m 2 q 21 d x 4 8ollowed by paclitaxel 175 mg/m 2 d1 x 4 Epirubicin 90 mg/m 2 + cyclophosphamide 600 mg/m 2 q 21 d x 4 8ollowed by paclitaxel 175 mg/m 2 d1 + gemcitabine 1,250 mg/m 2 d1 & 8 q 21 d x 4 ; R A N D O M I z A T I O N : : SMK:MB e= ;:se= HG <HNGMKR H? K:G=HFBz:MBHG, GH=:E sM:MNs, :ge, esMKHgeG Ke<eIMHK sM:MNs, IE:GGe= K:=BHMAeK:IR, hEr 32 sM:MNs. ; p:<EBM:xeE ?HEEHPe= ;R geF<BM:;BGe. (continued next page) 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 7 Adverse E88ect % o8 Patients EC 3T (n=1,554) EC 3GT (n=1,550) neNKHseGsHKR 4 5 FeOeK 3 5 cHGsMBI:MBHG : 2 3 dRsIGe: 2 3 dB:KKAe: 2 3 SMHF:MBMBs 2 2 aGeFB: : 1 2 tAKHF;H<RMHIeGB: < 1 1 cHNgA < 1 < 1 deeI OeBG MAKHF;HsBs < 1 1 SNIeK <B:E MAKHF;HIAEe;BMBs < 1 < 1 Ec 3t, eIBKN;B<BG, <R<EHIAHsIA:FB=e, I:<EBM:xeE; Ec 3Gt, eIBKN;B<BG, <R<EHIAHsIA:FB=e 3> I:<EBM:xeE, geF<BM:;BGe. : P d .05. Follow 3up: " Median follow-up: 34.9 months (interquartile range, 25.3 337.8 mo). " 10.8% of patients died. " 16.7% of patients relapsed. " No signi)cant difference was reported in DFS (hazard ratio [HR], 1.0 [95% con)dence interval {CI}, .8 31.2]; P =.96). " No signi)cant difference in OS occurred (HR, 1.1 [95% CI, .9 31.4]; P =.35). " Subgroup analyses were similar to overall analyses. concluSionS " Addition of gemcitabine to adjuvant chemotherapy with EC 3T, at this dose and schedule, con=ers no therapeutic advantage =or women with higher 3risk, early 3stage breast cancer. " No signi)cant differences in treatment effect realized across various subsets, including a preplanned analysis by ER (ie, strati cation =actor). " Toxicity of EC 3GT is acceptable for the adjuvant setting. rEFErEncES 1 aE;:BG kS, n:g Sm, c:E=eKBEEH 3rNBz G, eM :E. GeF<BM:;BGe IENs I:<EBM:xeE OeKsNs I:<EBM:xeE FHGHMAeK:IR BG I:MBeGMs PBMA FeM:sM:MB< ;Ke:sM <:G<eK :G= IKBHK :GMAK:<R<EBGe MKe:MFeGM. J Clin Oncol. 2008;26:3950 33957. 2 heG=eKsHG ic, beKKR da, deFeMKB Gd, eM :E. iFIKHOe= HNM<HFes ?KHF :==BGg seqNeGMB:E I:<EBM:xeE ;NM GHM ?KHF es<:E:MBGg =HxHKN;B<BG =Hse BG :G :=CON:GM <AeFHMAeK:IR KegBFeG ?HK I:MBeGMs PBMA GH=e 3IHsBMBOe IKBF:KR ;Ke:sM <:G<eK. J Clin Oncol . 2003;21:976 3983. Characteristic % o8 Patients a EC 3T (n=1,571) EC 3GT (n=1,570) me=B:G GH. :xBEE:KR GH=es (BGMeKqN:KMBEe K:Gge) 2 (1 35) 2 (1 35) Ec 3t, eIBKN;B<BG, <R<EHIAHsIA:FB=e, I:<EBM:xeE; Ec 3Gt, eIBKN;B<BG, <R<EHIAHsIA:FB=e 3> I:<EBM:xeE, geF<BM:;BGe; EcoG, E:sMeKG cHHIeK:MBOe oG<HEHgR GKHNI; pgr, IKHgesMeKHGe Ke<eIMHK. : uGEess HMAeKPBse GHMe=. rESultS E7fcacJ Dose :ntens:tJ " 89% of patients received 8 cycles. " Median dose intensity for EC 3T was 98%; for EC 3GT, 96%. " 85% of patients received optimal dose intensity (ie, > 85%: EC 3T, 89%; EC 3GT, 81%; P <.0001). " 10% of both EC 3T and EC 3GT patients required granulocyte colony 3stimulating =actor. Add:t:onal adjuGant therapJ " Tamoxifen was administered to women with estrogen receptor (ER)+ tumors a=ter computed tomography. " Of 860 postmenopausal women with ER+ (or weakly ER+) tumors, 60% of patients received aromatase inhibitors be=ore relapse. " Of 236 women with HER 32 +++ tumors, 34% received trastuzumab be=ore relapse. Deaths: 19 patients died < 3 months =ollowing treatment completion (EC 3T, 9; EC 3GT, 10), 14 o= whom died o= metastatic breast cancer (EC 3T, 7; EC 3GT, 7). Qual:tJ o7 l:7e: EC 3GT patients reported worse global health than EC 3T patients during treatment ( P =.03), but reported similar long 3term scores. Tox:c:tJ Adverse E88ect % o8 Patients EC 3T (n=1,554) EC 3GT (n=1,550) aEHIe<B: 96 95 neNMKHIeGB: : 27 34 mR:EgB:/:KMAK:EgB: 12 13 F:MBgNe : 10 13 iG?e<MBHG : 9 13 vHFBMBGg : 7 9 n:Nse: : 7 8 Baseline Characteristics (cont.) Toxicity (cont.) 8 El:g:b:l:tJ " Age: 65 years or older " Stage: T1 ( e 1 cm) to T4, N0 33, M0 " Any hormone receptor or HER 32 status " Performance status: 0 32 " Adequate hematologic, renal, hepatic function " Estimated survival: more than 5 years Pr:marJ endpo:nts : relapse 3=ree survival (local, metastases, died without relapse) SecondarJ endpo:nts " Overall survival (OS) " Treatment effect on QOL and functional status " Toxicity " Adherence to oral chemotherapy baSElinE charactEriSticS Characteristic % o8 Patients CMF/AC (n=326) Capecitabine (n=307) age 65 369 RK 70 379 RK 80+ RK 34 61 4 36 60 5 peK?HKF:G<e sM:MNs, 0 31 97 96 r:<e wABMe bE:<D 85 13 85 9 tNFHK sBze > 2 <F 51 61 nH=e IHsBMBOe 72 69 hHKFHGe Ke<eIMHK IHsBMBOe 66 68 hEr 32 IHsBMBOe 12 11 ac, =HxHKN;B<BG, <R<EHIAHsIA:FB=e; cmF, <R<EHIAHsIA:FB=e, FeMAHMKex:Me, fNHKHNK:<BE. Muss HB, BerrJ DL, C:rr:nc:one C, et al. Standard chemotherapJ (CMF or AC) Gersus capec:tab:ne :n earlJ 3stage breast cancer (BC) pat:ents aged 65 and older: results o7 CALGB/CTSU 49907 J Clin Oncol . 2008;26(suppl 1):8s. Abstract 507. backGround Several design =actors make this trial unique. " Trial 9s focus is older patients, who are underrepresented in clinical trials. " Oral capecitabine, proven effective in metastatic disease, is evaluated for early stage ef)cacy. " In addition to standard treatment outcomes, assessment includes quality of life (QOL), comorbidity, and functional status. " A unique microelectronic bottle 3cap device measures oral adherence. " A separate correlative study explores treatment outcome and toxicity to selected biological markers. StudJ Object:Ge : show nonin=eriority o= capecitabine to cyclophosphamide, methotrexate, and fuorouracil (CMF), or doxorubicin and cyclophosphamide (AC), in early 3stage breast cancer patients aged 65 years and older. Study dESiGn Multicenter, randomized, trial (CALBG/CTSU 49907) R A N D O M I z A T I O N Cyclophosphamide 100 mg/ m 2 d1 314, methotrexate 40 mg/ m 2 and fuorouracil 600 mg/ m 2 d1, 8 q 4 wk (CMF) x 6 cycles or Doxorubicin 60 mg/ m 2 and cyclophosphamide 600 mg/ m 2 d1 q 3 wk (AC) x 4 cycles Capecitabine 1,000 mg BID d1 314 q 3 wk Strati cation " Age 3 65 369 yr 3 70 380 yr 3 80+ yr " Performance status 3 0 31 3 2 " HER 32 status 3 Positive 3 Negative 3 Unknown Con7erence Proceed:ngs: Breast Cancer 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 9 rESultS E7fcacJ F:rst analJs:s " Observed hazard ratio (HR), .53 " Probable HR less than .80, 90% " Met criteria for stopping accrual, as capecitabine is likely in=erior to CMF/AC " Median follow 3up: 2.4 years Planned courses rece:Ged " CMF: 62% " AC: 92% " Capecitabine: 80% Relapse 3Free and Overall Survival Characteristic % o8 Patients CMF/AC (n=326) Capecitabine (n=307) aEBOe PBMAHNM =Bse:se 89 80 EOeGMs lH<:E oGER dBsM:GM ± EH<:E dBe=, GH =Bse:se 11 2 5 5 20 6 8 6 dBe= 7 12 c:Nse H? =e:MA bKe:sM <:G<eK tKe:MFeGM neBMAeK uGDGHPG 2 0 4 1 6 <1 5 1 ac, =HxHKN;B<BG, <R<EHIAHsIA:FB=e; cmF, <R<EHIAHsIA:FB=e, FeMAHMKex:Me, fNHKHNK:<BE. Using Cox proportional hazard model =or multivariate analysis, study determined that patients are more likely to relapse i=: " Treated with capecitabine (HR, 2.09 [95% con)dence interval {CI}, 1.4 33.2]; P =.0006) " Tumors are larger (HR, 1.47 [95% CI, 1 32.2]; P =.048) " Several lymph nodes are positive (HR, 1.35 [95% CI, 1.1 31.7]; P =.0044) " Patients have hormone receptor negative disease (HR, 3.04 [95% CI, 2 34.6]; P <.0001) " Treated with capecitabine, and have hormone negative disease (HR, 4.39 [95% CI, 2.9 36.7]; P <.0001). Univariate analysis (log rank test) showed that both CMF and AC are signi cantly superior to capecitabine in relapse 3 =ree survival ( P =.0009). Using Cox proportional hazard model =or multivariate analysis, study determined that OS is diminished =or patients who: " Are treated with capecitabine (HR, 1.85 [95% CI, 1.1 33.1]; P =.019). " Have larger tumors (HR, 1.75 [95% CI, 1.1 32.8]; P =.0088). " Have hormone 3receptor negative disease (HR, 2.62 [95% CI, 1.6 34.4]; P =.0002) Univariate Analysis (log rank test) showed that both CMF and AC are signi cantly superior to capecitabine in increasing overall survival ( P =.019). Tox:c:tJ Grade 3/4 Adverse Event % o8 Patients CMF (n=132) AC (n=183) Capecitabine (n=299) heF:MHEHgB< 52 54 3 nHGAeF:MHEHgB< 40 24 33 tHM:E 69 59 34 ac, =HxHKN;B<BG, <R<EHIAHsIA:FB=e; cmF, <R<EHIAHsIA:FB=e, FeMAHMKex:Me, fNHKHNK:<BE. " Drug 3related deaths: 2 capecitabine patients " Transfusion: 2 AC patients " Congestive heart failure: 1 CMF patient " Myelodysplasia: 1 capecitabine patient concluSionS " AC/CMF is superior to capecitabine for both relapse 3 =ree and overall survival. " Toxicity is moderate for all regimens (capecitabine produced 2 drug 3related deaths). " Unplanned subset analysis revealed major bene)t of CMF/AC =or patients with receptor 3negative tumors. 10 backGround Bevacizumab " A monoclonal antibody to vascular endothelital growth =actor (VEGF) that inhibits tumor angiogenesis " Signi)cantly improves progression 3free survival (PFS) when combined with paclitaxel as rst 3line therapy o= metastatic breast cancer (mBC) (phase 3 E2100 study). 1 Docetaxel is widely used in treatment o= mBC. StudJ Object:Ge : compare e= cacy o= bevacizumab + docetaxel with docetaxel + placebo as rst 3line therapy in locally advanced or mBC. M:les D, Chan A, Rom:eu G, et al. Random:zed, double 3bl:nd, placebo 3controlled phase iii studJ o7 beGac:zumab (B) w:th docetaxel (D) or docetaxel w:th placebo (PL) as frst 3l:ne therapJ 7or pat:ents w:th locallJ recurrent or metastat:c breast cancer (mBC): AvADO. J Clin Oncol. 2008;26(suppl 2):1008s. Abstract LBA1011. RandomiLation (N=705) a Strati cation 8actors: " Region " Prior taxane/time to relapse since adjuvant chemotherapy " Measurable disease " Hormone receptor status All patients given option to receive bevaciLumab with 2nd line chemotherapy Treat with placebo/ bevaciLumab to disease progression Docetaxel 100 mg/m 2 q 3 wk x 9 cycles b Docetaxel 100 mg/m 2 q 3 wk + bevaciLumab 7.5 mg/kg q 3 wk x 9 cycles b Docetaxel 100 mg/m 2 q 3 wk + bevaciLumab 15 mg/kg q 3 wk x 9 cycles b : reqNBKe= GH. H? I:MBeGMs. ; E:KER =Bs<HGMBGN:MBHG P:s IeKFBMMe=. El:g:b:l:tJ " Women aged 18 years and older " Eastern Cooperative Oncology Group (ECOG) per=ormance status (PS), 0 31 " No prior chemotherapy for locally recurrent or mBC " Prior adjuvant chemotherapy permitted if relapse occurred 6 or more months since last dose ( e 12 mo, i= taxane regimen) " HER 32 negative Pr:marJ endpo:nt : PFS SecondarJ endpo:nts " Overall response rate " Duration of response " Time to treatment failure " Overall survival " Safety " Quality of life Con7erence Proceed:ngs: Breast Cancer Study dESiGn Multicenter, randomized, double 3blind, placebo 3controlled phase 3 trial (AVADO) " Designed to detect PFS hazard ratio of .7, with a median of 6 months vs 8.6 months " Compare between each combination arm with control, not between 2 combination arms " US Food and Drug Administration (FDA) secondary analysis with data sensor 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 11 baSElinE charactEriSticS Characteristics % o8 Patients a Placebo + Docetaxel (n=241) Bev 7.5 ; + Docetaxel (n=248) Bev 15 ; + Docetaxel (n=241) me=B:G :ge, RK (K:Gge) 55 (29 383) 54 (26 383) 555 (27 376) EcoG pS 0 1 62 38 61 39 61 39 Er/pr IHsBMBOe 78 78 76 dBse:se 3?Kee BGMeKO:E e 12 FH 82 75 81 a=CNO:GM <AeFHMAeK:IR t:x:Ge aGMAK:<R<EBGe 65 15 55 65 15 53 68 17 55 e 3 meM:sM:MB< sBMe 41 49 49 meM:sM:MB< sBMe bHGe lBOeK lNGg 59 50 38 60 40 42 55 46 48 me:sNK:;Ee dBse:se 86 81 83 beO, ;eO:<BzNF:;; EcoG, E:sMeKG cHHIeK:MBOe oG<HEHgR GKHNI; Er, esMKHgeG Ke<eIMHK; pr, IKHgesMeKHGe Ke<eIMHK; pS, IeK?HKF:G<e sM:MNs. : uGEess HMAeKPBse GHMe=. ; Fg/Dg q 3 PD. rESultS E7fcacJ : median =ollow 3up was 10.2 months (range, 0 317.5 mo) Progression 3Free Survival a Placebo + Docetaxel (n=241) Bev 7.5 b + Docetaxel (n=248) Bev 15 b + Docetaxel (n=247) me=B:G (FH) 8.0 8.7 8.8 h:z:K= K:MBH (95% ci) P v:ENe na na .79 (.63 3.98) .0318 .72 (.57 3.90) .0099 beO, ;eO:<BzNF:;; ci, <HG =eG<e BGMeKO:E; na, GHM :IIEB<:;Ee. : SA:Ie H? <NKOe BGfNeG<e= ;R MBFBGg H? =Bse:se eO:EN:MBHG. ; Fg/Dg q 3 PD. PFS subgroup analJs:s " Evaluated estrogen/progesterone receptor status, prior adjuvant chemotherapy, prior taxane therapy, and measurable disease at baseline " Results similar to overall population PFS analysis Response (Patients With Measurable Disease) % o8 Patients Placebo + Docetaxel (n=207) Bev 7.5 a + Docetaxel (n=201) Bev 15 a + Docetaxel (n=206) orr P v:ENe Os <HGMKHE 44 55 .0295 63 .0001 besM KesIHGse cr pr Sd pd 1 44 39 12 3 52 35 5 1 62 25 4 cr, <HFIEeMe KesIHGse; orr, HOeK:EE KesIHGse K:Me; pd, I:KMB:E =Bse:se; pr, I:KMB:E KesIHGse; Sd, sM:;Ee =Bse:se. : Fg/Dg q 3 PD. Survival Data a Placebo + Docetaxel (n=241) Bev 7.5 b + Docetaxel (n=248) Bev 15 b + Docetaxel (n=247) de:MAs, GH. H? I:MBeGMs (%) 50 (21) 49 (20) 37 (15) me=B:G oS, FH hr (95% cE) nr na nr .92 (.62 31.37) nr .68 (.45 31.04) 1 3RK sNKOBO:E, % nH. H? I:MBeGMs sMBEE :M KBsD 73 63 78 73 83 79 ci, <HG =eG<e BGMeKO:E; na, GHM :IIEB<:;Ee; nr, GHM Ke:<Ae=; oS, HOeK:EE sNKOBO:E. : cNM H?? ?HK sNKOBO:E :G:ERsBs: 24 FH :?MeK E:sM I:MBeGM Ke<KNBMe=; e:KER =:M:, Gee=s MH F:MNKe. ; Fg/Dg q 3 PD. Tox:c:tJ AE % o8 Patients Placebo + Docetaxel (n=233) Bev 7.5 c + Docetaxel (n=250) Bev 15 c + Docetaxel (n=247) aGR aE 99.6 100.0 99.6 aGR gK:=e e 3 aE 67.0 74.8 74.1 aEs Ee:=BGg MH =e:MA : 2.6 1.6 1.6 aEs Ee:=BGg MH =Bs<HGMBGMN:MBHG H? ; dH<eM:xeE beO:<BzNF:;/IE:<e;H 24.0 11.2 20.8 8.0 24.3 11.7 aE, :=OeKse eOeGM. : dNKBGg sMN=R. ; nHM FNMN:EER ex<ENsBOe. < Fg/Dg q 3 PD. 12 Gnant M, Ml:ner:tsch B, Sch:pp:nger W, et al. AdjuGant oGar:an suppress:on comb:ned w:th tamox:7en or anastrozole, alone or :n comb:nat:on w:th zoledron:c ac:d, :n premenopausal women w:th endocr:ne 3 respons:Ge, stage i and ii breast cancer: frst e7fcacJ results 7rom ABCSG 312. J Clin Oncol. 2008;26 (suppl pt 2):1006s. Abstract LBA4. backGround Aromatase inhibitors (AIs) " AIs have superior ef)cacy compared with tamoxifen =or postmenopausal endocrine 3responsive breast cancer, when administered up=ront or a=ter tamoxi=en therapy. 1 37 " Anastrozole plus goserelin signi)cantly reduces measured estrogen levels in premenopausal women who experience disease progression during treatment with goserelin plus tamoxi=en. 8 Zoledronic acid inhibits tumor cell metastasis by: " Interfering with adhesion " Inhibiting tumor growth " Inducing apoptosis " Inhibiting angiogenesis " Stimulating immune response StudJ Object:Ge : determine whether AIs, compared with tamoxi=en, improve outcomes in premenopausal breast cancer patients, and i= bisphosphonates added to endocrine therapy improve outcomes beyond endocrine therapy alone. Selected Key Grade e 3 AE a % o8 Patients Placebo + Docetaxel (n=233) Bev 7.5 b + Docetaxel (n=250) Bev 15 b + Docetaxel (n=247) dB:KKAe: 3.4 6.8 6.9 F:MBgNe 5.2 8.4 6.5 p:EF:K 3IE:GM:K eKRMAeF: .9 5.2 6.1 mN<Hs:E BGf:FF:MBHG .4 4.0 4.9 peKBIAeK:E seGsHKR GeNKHI:MAR 1.7 3.2 4.5 SMHF:MBMBs .4 2.8 3.2 mR:EgB: .9 1.2 3.6 SDBG ex?HEB:MBHG 0 2.4 1.2 aGeFB: 2.6 .4 1.2 iG?e<MBHG 3.0 .8 .4 aE, :=OeKse eOeGM. : wBMA e 2% =B??eKeG<e ;eMPeeG :KFs. ; Fg/Dg q 3 PD. " Grade e 3 =ebrile neutropenia and in=ection were similar between arms. " Grade e 3 venous thromboembolism was higher with docetaxel alone (3.4% vs 1.2% [bevacizumab 7.5/ docetaxel and bevacizumab 15/docetaxel]). " Grade e 3 hypertension, wound healing, and gastrointestinal per=oration were similar between arms. concluSionS " Results con)rmed the clinical bene)t of combining rst 3line bevacizumab with taxanes =or patients with HER 32 negative metastatic breast cancer. " Both 7.5 mg/kg and 15 mg/kg bevacizumab, combined with docetaxel, signi cantly increased PFS and response rate, compared with docetaxel alone. " OS data have not yet matured. " No new safety signals were detected, and bevacizumab had limited impact on toxicity pro le o= docetaxel 100 mg/m 2 . rEFErEncES 1 mBEEeK k, w:Gg m, GK:EHP j, eM :E. p:<EBM:xeE IENs ;eO:<BzNF:; OeKsNs I:<EBM:xeE :EHGe ?HK FeM:sM:MB< ;Ke:sM <:G<eK. N Engl J Med . 2007;357: 2666 32676. Con7erence Proceed:ngs: Breast Cancer 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 13 El:g:b:l:tJ " Endocrine 3responsive (estrogen receptor/progesterone receptor positive) " Stages I and II " Less than 10 positive lymph nodes " No chemotherapy except neoadjuvant Pr:marJ endpo:nt : Disease 3=ree survival (DFS) rate, which includes: " Local recurrence " Contralateral breast cancer " Distant recurrence " Secondary carcinoma " Death SecondarJ endpo:nts p " Recurrence 3free survival (RFS), which includes: 3 Local recurrence 3 Contralateral breast cancer 3 Distant recurrence 3 Secondary carcinoma " Overall survival (OS) " Safety ExploratorJ endpo:nt : bone metastases 3=ree survival Study dESiGn Academic, randomized, phase 3 trial conducted by Austrian Breast Cancer Study Group (ABCSG 312) baSElinE charactEriSticS Characteristic % o8 Patients Tamoxi8en (n=452) Tamoxi8en + zoledronic Acid (n=449) AnastroLole (n=450) AnastroLole + zoledronic Acid (n=449) me=B:G :ge, RK 45.5 45.3 45 44.5 SM:ge t1 e t2 75.1 22.0 74.6 21.8 77.0 20.6 75.5 21.6 nH=e neg:MBOe pHsBMBOe 66.9 30.2 65.7 30.7 67.0 30.8 67.3 30.1 re<eIMHK IHsBMBOBMR Er+/++ Er+++ pr+/++ pr+++ 48.0 45.6 46.9 41.3 47.3 45.0 44.6 44.8 48.3 46.0 45.6 44.5 47.4 46.1 40.6 48.8 GK:=BGg 20.7 19.8 21.5 21.8 bKe:sM <HGseKO:MBHG 79.6 79.5 80.4 79.6 neH:=CNO:GM <AeFHMAeK:IR 5.3 5.1 5.3 5.8 peK 3IKHMH<HE MKe:MFeGM 91.6 90.4 92.5 92.2 Er, esMKHgeG Ke<eIMHK; pr, IKHgesMeKHGe Ke<eIMHK. Tamoxi8en 20 mg/d x 3 yr Tamoxi8en 20 mg/d + Loledronic acid 4 mg q 6 mo x 3 yr AnastroLole 1 mg/d x 3 yr AnastroLole 1 mg/d + Loledronic acid 4 mg q 6 mo x 3 yr RANDOMIzATION Surgery (+ radiotherapy) Goserelin 3.6 mg q 28 d x 3 yr 14 rESultS E7fcacJ El:g:b:l:tJ DFS " Median follow 3up: 47.8 months " March 2008: 137 )rst DFS events, 42 deaths 3 Locoregional relapse: 30 3 Distant relapse events: 70 (including 40 bone metastasis events) 3 Contralateral breast cancer events: 16 3 New nonbreast primary events: 19 " Overall 4 3year DFS rate: 92% " No signi)cant difference between tamoxifen and anastrozole (hazard ratio [HR], 1.096 [con dence interval {CI} .78 31.53]; P =.593) " Zoledronic acid signi)cantly improves DFS compared with endocrine therapy alone (HR, .643 [95% CI, .46 3.91]; P =.011) RFS " No signi)cant difference is found between tamoxifen and anastrozole (HR, 1.116 [95% CI, .80 31.58]; P =.529). " Zoledronic acid signi)cantly improves RFS, compared with endocrine therapy alone (HR, .653 [95% CI, .48 3.92]; P =.014). OS " Four 3year OS rate: 98% " No signi)cant difference between tamoxifen and anastrozole (HR, 1.791 [95% CI, .95 33.37]; P =.065) " No signi)cant difference between zoledronic acid plus endocrine therapy, and endocrine therapy alone (HR, .595 [95% CI, .32 31.11]; P =.101) First DFS Event No. o8 Patients Tamoxi8en (n=900) AnastroLole (n=903) No zoledronic Acid (n=904) zoledronic Acid (n=899) de:MA PBMAHNM IKBHK Ke<NKKeG<e 1 1 2 0 Se<HG=:KR F:EBgG:G<R 9 10 10 9 cHGMK:E:MeK:E ;Ke:sM <:G<eK 10 6 10 6 dBsM:GM Ke<NKKeG<e 29 41 41 29 lH<HKegBHG:E Ke<NKKeG<e 16 14 20 10 dFS, =Bse:se 3?Kee sNKOBO:E. No di==erences observed between zoledronic acid and control treatment in exploratory analysis o= DFS in subgroups. Tox:c:tJ Adverse Event % o8 Patients P Value Tamoxi8en (n=435) Tamoxi8en + zoledronic Acid (n=434) AnastroLole (n=436) AnastroLole + zoledronic Acid (n=439) aKMAK:EgB: 11.5 14.5 24.7 33.3 <.0001 bHGe I:BG 20.8 29.4 28.3 41.1 <.0001 FeOeK 2 7.6 2.4 10.2 <.0001 deIKessBHG, sEeeI =BsMNK;:G<es 15.5 16.5 21.4 17.8 .110 peKBH=HGM:E =Bse:se : 1.1 .7 0 1.3 .054 Con7erence Proceed:ngs: Breast Cancer : nH <HG KFe= <:ses H? HsMeHGe<KHsBs H? MAe C:P. 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 15 Serious Adverse Event % o8 Patients P Value Tamoxi8en (n=435) Tamoxi8en + zoledronic Acid (n=434) AnastroLole (n=436) AnastroLole + zoledronic Acid (n=439) aKMAK:EgB: 0 .2 0 .2 .374 bHGe I:BG 0 0 0 .2 .499 FeOeK .2 .2 .2 .4 .882 FK:<MNKe 1.3 .9 .9 1.6 .747 tAKHF;HsBs .7 1.1 0 0 .012 uMeKBGe IHERI 8.9 11.4 1.6 1.1 <.0001 peKBH=HGM:E =Bse:se : 0 .2 0 .2 .374 : nH <HG KFe= <:ses H? HsMeHGe<KHsBs H? MAe C:P. Zoledronic acid combined with adjuvant endocrine therapy toxicity " Adverse effects as expected " Not signi)cantly associated with serious adverse events " No con)rmed cases of osteonecrosis of jaw " No renal toxicity concluSion " After 4 years of follow 3up, 92% DFS and 98% RFS =or overall trial cohort supports growing evidence that a low 3 and intermediate 3risk patient with endocrine 3responsive early breast cancer can be spared the adverse e==ects o= cytotoxic therapy a=ter locoregional treatment. " Zoledronic acid (4 mg q 6 mo) signi)cantly improves clinical outcomes beyond those achieved with endocrine therapy alone. " Zoledronic acid bene)t is seen in and outside bone. 3 Contralateral breast cancer is decreased. 3 Locoregional recurrence is reduced. 3 Distant nonbone recurrence is decreased. " Adverse effects of zoledronic acid are acceptable. " Optimal dose, schedule, and treatment duration of zoledronic acid must be addressed in ongoing clinical trials. " Adjuvant treatment with zoledronic acid should be considered in order to improve the standard o= care in premenopausal women with breast cancer. rEFErEncES 1 hHPeEE a, cNzB<D j, b:NF m, eM :E. resNEMs H? MAe atac (aKBFB=ex, t:FHxB?eG, aEHGe HK BG cHF;BG:MBHG) MKB:E :?MeK <HFIEeMBHG H? 5 Re:Ks 9 :=CNO:GM MKe:MFeGM ?HK ;Ke:sM <:G<eK. Lancet . 2005;365:60 362. 2 bKe:sM iGMeKG:MBHG:E GKHNI (biG) 1 398 cHEE:;HK:MBOe GKHNI, tAüKEBF:GG b, kesA:OB:A a, eM :E. a <HFI:KBsHG H? EeMKHzHEe :G= M:FHxB?eG BG IHsMFeGHI:Ns:E e:KER ;Ke:sM <:G<eK. N Engl J Med . 2005;353:2747 32757. 3 cH:Mes a, kesA:OB:A a, tAüKEBF:GG b, eM :E. FBOe Re:Ks H? EeMKHzHEe <HFI:Ke= PBMA M:FHxB?eG :s BGBMB:E :=CNO:GM MAeK:IR ?HK IHsMFeGHI:Ns:E PHFeG PBMA eG=H<KBGe 3KesIHGsBOe e:KER ;Ke:sM <:G<eK: NI=:Me H? sMN=R biG 1 398. J Clin Oncol. 2007;25:486 3492. 4 cHHF;es rc, h:EE E, GB;sHG lj, eM :E. a K:G=HFBze= MKB:E H? exeFesM:Ge :?MeK MPH MH MAKee Re:Ks H? M:FHxB?eG MAeK:IR BG IHsMFeGHI:Ns:E PHFeG PBMA IKBF:KR ;Ke:sM <:G<eK. N Engl J Med . 2004;350:1081 31092. 5 cHHF;es rc, kBE;NKG lh, SGHP=HG cF, eM :E. SNKOBO:E :G= s:?eMR H? exeFesM:Ge OeKsNs M:FHxB?eG :?MeK 2 33 Re:Ks 9 M:FHxB?eG MKe:MFeGM (iGMeKgKHNI ExeFesM:Ge SMN=R): : K:G=HFBse= <HGMKHEEe= MKB:E. Lancet . 2007;362:559 3570. 6 j:Desz r, jHG:M w, GG:GM m, eM :E. SPBM<ABGg H? IHsMFeGHI:Ns:E PHFeG PBMA eG=H<KBGe 3KesIHGsBOe e:KER ;Ke:sM <:G<eK MH :G:sMKHzHEe :?MeK 2 Re:Ks 9 :=CNO:GM M:FHxB?eG: <HF;BGe= KesNEMs H? abScG MKB:E 8 :G= arno 95 MKB:E. Lancet . 2005;36:455 3462. 7 GHss p, iGgEe jn, m:KMBGH S, eM :E. r:G=HFBze= MKB:E H? EeMKHzHEe ?HEEHPBGg M:FHxB?eG :s exMeG=e= :=CNO:GM MAeK:IR BG Ke<eIMHK 3IHsBMBOe ;Ke:sM <:G<eK: NI=:Me= G=BGgs ?KHF ncic ctG ma.17. J Natl Cancer Inst . 2005;97:1262 3 1271. 8 FHKP:K= dp, cAeNGg kl, j:<DsHG l, eM :E. cEBGB<:E :G= eG=H<KBGe =:M: ?HK gHseKeEBG IENs :G:sMKHzHEe :s se<HG= 3EBGe eG=H<KBGe MAeK:IR ?HK IKeFeGHI:Ns:E :=O:G<e= ;Ke:sM <:G<eK. Br J Cancer . 2004;90:590 3594. 16 Study dESiGn International, multicenter, randomized, controlled, phase 3 trial backGround Trastuzumab " Inactivates survival signaling through the PI3 kinase pathway " Resistance occurs with continued signaling through the PI3 and MAP kinase pathways when any o= the =ollowing occur 3 Loss o= the HER 32 extracellular domain 3 Masking o= HER 32 by MUC4 3 Loss o= p10 with activation o= the PI3 kinase pathway 3 HER 32 heterodimerization " Monotherapy clinical studies not feasible in patients whose tumors recently progressed on trastuzumab Lapat:n:b " Blocks intracellular signaling of the HER 32 kinase at the ATP intracellular binding site by: 3 Blocking HER 32 homodimers and HER 31/HER 32 heterodimers 3 Blocking HER 32 signalling through the p95 when the HER 32 extracellular domain has been cleaved 3 Blocking HER 32 signaling when MUC4 is present or p10 is deleted " Inhibits the growth of growth of breast cancer cell lines that are resistant to trastuzmab 1 " Has synergistic activity in HER 32+ breast cancer cell lines when combined with trastuzumab " Is effective as monotherapy 3 Trastuzumab 3naïve patients: overall response rate (ORR), 24% 328% 2,3 3 Trastuzumab 3pretreated infammatory breast cancer patients: ORR, ~40% 4 3 Heavily 3pretreated HER 32+ metastatic breast cancer (mBC) patients: ORR, ~2% 324% 5,6 StudJ Object:Ge : determine i= more complete HER 32 blockade in treatment o= mBC improves patient outcomes. O 9ShaughnessJ J, Blackwell KL, Burste:n H, et al. A random:zed studJ o7 lapat:n:b alone or :n comb:nat:on w:th trastuzumab :n heaG:lJ pretreated HER 32+ metastat:c breast cancer progress:ng on trastuzumab therapJ. J Clin Oncol. 2008;26(suppl pt 1):44s. Abstract 1015. Con7erence Proceed:ngs: Breast Cancer Strati cation " Visceral disease " Hormone receptor status Lapatinib 1,500 mg/d PO (n=148) Lapatinib 1,000 mg/d PO + TrastuLumab 4 mg/kg 3> 2mg/kg IV q wk (n=148) R A N D O M I z A T I O N Crossover i8 progressive disease alter 4 wk therapy (n=73) 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 17 El:g:b:l:tJ " HER 32+ (diagnosed by +uorescence in situ hybridization [FISH]+ or immunohistochemistry [IHC3)]+) mBC " Progression on 3 Anthracycline 3 Taxane 3 Trastuzumab " Progression on most recent trastuzumab regimen Pr:marJ endpo:nt : investigator 3determined progression 3=ree survival (PFS) SecondarJ endpo:nts " Overall survival " ORR " Clinical bene)t rate " Duration of response " Time to response " Safety " Quality of life baSElinE charactEriSticS Characteristic % o8 Patients a Lapatinib (n=148) Lapatinib + TrastuLumab (n=148) me=B:G :ge, RK (K:Gge) 51 (29 378) 52 (26 381) EcoG IeK?HKF:G<e sM:MNs 0 1 2 47 49 4 54 41 5 me=B:G IKBHK <AeFHMAeK:IR KegBFeGs 4 5 p:MBeGMs Ke<eBOBGg e 6 IKBHK KegBFeGs 28 34 me=B:G IKBHK MK:sMNzNF:; KegBFeGs ?HK Fbc 3 3 me=B:G MBFe ?KHF E:sM MK:sMNzNF:; =Hse, = 25 27 hEr 32+ 99 99 Er 3 :G= pgr 3 51 51 vBs<eK:E =Bse:se 74 71 EcoG, E:sMeKG cHHIeK:MBOe oG<HEHgR GKHNI; Er, esMKHgeG Ke<eIMHK; Fbc, FeM:sM:MB< ;Ke:sM <:G<eK; pgr, IKHgesMeKHGe Ke<eIMHK. : uGEess HMAeKPBse GHMe=. rESultS E7fcacJ E8 cacy Measure Lapatinib (n=148) Lapatinib + TrastuLumab (n=148) P Value resIHGse K:Me, % (95% ci) 6.9 (3.4 312.3) 10.3 (5.9 316.4) o==s K:MBH (95% ci) 1.5 (.6 3 3.9) .46 cEBGB<:E ;eGe M K:Me, % (95% ci) 12.4 (7.5 318.9) 24.7 (17.9 332.5) o==s K:MBH (95% ci) 2.2 (1.2 34.5) .01 pKHgKesse= HK =Be=, GH. H? I:MBeGMs 128 127 me=B:G MBFe MH IKHgKessBHG, PD 8.1 12.0 h:z:K= K:MBH (95% ci) .73 (.57 3.93) .008 6 3FH pFS K:Me, % 13 28 dBe=, GH. H? I:MBeGMs 69 56 me=B:G MBFe MH =e:MA, PD 39 51.6 h:z:K= K:MBH (95% ci) .75 (.53 31.07) .106 6 3FH oS K:Me, % 70 80 12 3FH oS K:Me, % 36 45 ci, <HG =eG<e BGMeKO:E; oS, HOeK:EE sNKOBO:E; pFS, IKHgKessBHG 3?Kee sNKOBO:E. Factors signi cantly infuencing PFS " Combination therapy vs monotherapy, (hazard ratio [HR], .72 [95% con)dence interval {CI}, .56 3.92]; P =.0095) " Eastern Cooperative Oncology Group performance status (0 vs e 1), (HR, .63 [95% CI, .48 3.81]; P =.0005) " Liver metastases (no vs yes), (HR, .72 [95% CI, .56 3.94]; P =.02) " Number of metastatic sites (< 3 vs e 3), (HR, .73 [95% CI, .56 3.95]; P =.02) Lapatinib and trastuzumab combined therapy " 28% Reduction in PFS (HR, .72 [95% CI, .56 3.92]; P =.0095) " 29% Reduction in death (HR, .71 [95% CI, .50 31.01]; P =.0596) " Both adjusted for performance status and extent of disease 18 Tox:c:tJ Adverse Event a % o8 Patients Lapatinib b (n=146) Lapatinib + TrastuLumab (n=149) dB:KKAe: c GK:=e 3 HK 4 48 7 60 7 r:sA 29 22 n:Nse: 28 28 F:MBgNe 19 21 vHFBMBGg 18 14 dRsIGe: 10 12 aGHKexB: 10 11 he:=:<Ae 9 10 cHNgA 10 5 : iG<B=eG<e e 10%. ; Ex<EN=es eOeGMs H<<NKKBGg =NKBGg <KHssHOeK IA:se. Cardiac Event % o8 Patients Lapatinib (n=146) Lapatinib + TrastuLumab (n=149) deOeEHIe= eOeGM a SRFIMHF:MB< 5 1 8 2 reE:Me= MH MAeK:IR 3 8 resHEOe= ;R =:M: <NM 3H?? ; 4 5 F:M:E < 0 1 : 2 p:MBeGMs A:= > 1 H<<NKKeG<e. ; 3 p:MBeGMs Ke<HOeKe= PABEe KeF:BGBGg HG MKe:MFeGM. < c:K=B:< ?:BENKe; <:Nse H? =e:MA, INEFHG:KR MAKHF;HeF;HEBsF. concluSionS " Lapatinib, in combination with trastuzumab, is an e==ective treatment =or HER 32+ mBC progressing on (or a=ter) trastuzumab, which con rms preclinical synergy. " Treatment with this combination: 3 Signi cantly improves PFS 3 Doubles clinical bene t rate 3 Shows a trend toward improved overall survival. " Study con)rms activity of single agent lapatinib, despite several prior trastuzumab regimens. " Combination has predictable and manageable toxicity. rEFErEncES 1 kHGe<GR GE, pegK:F md, veGD:Mes:G n, eM :E. a<MBOBMR H? MAe =N:E DBG:se BGAB;BMHK E:I:MBGB; (Gw5272016) :g:BGsM hEr 32 3HOeKexIKessBGg :G= MK:sMNzNF:; 3MKe:Me= ;Ke:sM <:G<eK <eEEs. Cancer Res . 2006;66:1630 31639. 2 GHFez hl, dHO:E dc, cA:Oez ma, eM :E. E? <:<R :G= s:?eMR H? E:I:MBGB; :s KsM 3EBGe MAeK:IR ?HK EK;b2 3:FIEB e= EH<:EER :=O:G<e= HK FeM:sM:MB< ;Ke:sM <:G<eK. J Clin Oncol. 2008;26:2999 33005. 3 SE:FHG d, GHFez hl, k:;;BG:O:K FF, eM :E. r:G=HFBze= sMN=R H? I:zHI:GB; + E:I:MBGB; Os. E:I:MBGB; :EHGe BG I:MBeGMs PBMA hEr 32 3IHsBMBOe :=O:G<e= HK FeM:sM:MB< ;Ke:sM <:G<eK. J Clin Oncol. 2008;26(sNIIE IM 1):45s. a;sMK:<M 1016. 4 jHAGsMHG S, tKN=e:N m, k:N?F:G b, eM :E. pA:se ii sMN=R H? IKe=B<MBOe ;BHF:KDeK IKH Ees ?HK KesIHGse M:KgeMBGg ANF:G eIB=eKF:E gKHPMA ?:<MHK Ke<eIMHK 2 (hEr 32) BG :=O:G<e= BGf:FF:MHKR ;Ke:sM <:G<eK PBMA E:I:MBGB; FHGHMAeK:IR. J Clin Oncol. 2008;26:1066 31072. 5 bE:<DPeEE kl, bNKsMeBG h, pegK:F m, eM :E. deMeKFBGBGg KeEeO:GM ;BHF:KDeKs ?KHF MBssNe :G= seKNF MA:M F:R IKe=B<M KesIHGse MH sBGgEe :geGM E:I:MBGB; BG MK:sMNzNF:; Ke?K:<MHKR FeM:sM:MB< ;Ke:sM <:G<eK. J Clin Oncol. 2005;23(sNIIE IM 1):193s. a;sMK:<M 3004. 6 iP:M: h, tHB m, FNCBP:K: y, eM :E. pA:se ii <EBGB<:E sMN=R H? E:I:MBGB; (Gw572016) BG I:MBeGMs PBMA :=O:G<e= HK FeM:sM:MB< ;Ke:sM <:G<eK. Breast Cancer Res Treat . 2006;100 (sNIIE 1):s68. a;sMK:<M 1091. van Cutsem E, Lang i, D 9haens G, et al. KRAS status and e7fcacJ :n the frst 3l:ne treatment o7 pat:ents w:th metastat:c colorectal cancer (mCRC) treated w:th FOLFiRi w:th or w:thout cetux:mab: the CRySTAL exper:ence. J Clin Oncol. 2008;26(suppl, pt 1):5s. Abstract 2. colorEctal cancEr backGround KRAS " KRAS protein cycles between active and inactive =orms, and =unctions as a binary switch =or signal transduction =rom cell sur=ace receptors, including epidermal growth =actor receptor (EGFR). " Mutations cause KRAS to be locked in the con d position. " Mutated KRAS continues to signal RAS/RAF/MEK pathway, leading to cell proli=eration, without activating a cell sur=ace receptor, such as EGFR. Con7erence Proceed:ngs: Colorectal Cancer 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 19 patiEnt charactEriSticS Characteristic % o8 Patients KRAS WT (n=348) KRAS MT (n=192) age < 65 RK 65.8 59.9 pKeOBHNs :=CNO:GM MAeK:IR 21.6 12.5 iGOHEOe= =Bse:se sBMes d 2 85.3 83.3 lBOeK 3EBFBMe= =Bse:se 19.3 21.9 mt, FNM:GM MRIe; wt, PBE= MRIe. EGFR inhibitors used in treatment o= metastatic colorectal cancer (mCRC) include cetuximab and panitumumab. Several nonrandomized studies support the correlation between KRAS mutations and lack o= response to EGFR inhibitors, such as cetuximab and panitumumab, in chemore=ractory mCRC. 1 36 Two randomized studies o= EGFR inhibitors demonstrate in=erior progression =ree survival (PFS) in patients with KRAS mutant tumors. 7,8 StudJ Object:Ge : determine the e==ect o= KRAS status on response rate and PFS in mCRC patients receiving rst 3line FOLFIRI treatment, with and without cetuximab. Study dESiGn El:g:b:l:tJ " Unresectable, EGFR 3expressing, mCRC " No previous chemotherapy for metastatic disease; adjuvant chemotherapy (no irinotecan) discontinued 6 or more months be=ore randomization Pr:marJ endpo:nt : PFS Selected secondarJ endpo:nts " Overall response rate (ORR) " Disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) " Overall survival (OS) " Safety E= cacy analysis was repeated using only the KRAS assessable patient population. Cetuximab ; + FOLFIRI (n=277) FOLFIRI (n=263) KRAS WT, (n=172) KRAS evaluable (n=540) KRAS MT, (n=105) KRAS WT, (n=176) KRAS MT, (n=87) EGFR 3expressing mCRC (N=1,198) : EGFr, eIB=eKF:E gKHPMA ?:<MHK Ke<eIMHK; FolFiri, BKBGHMe<:G 180 Fg/F 2 iv, ?HEBGB< :<B= ?HEEHPe= ;R fNHKHNK:<BE 400 Fg/F 2 iv ;HENs, MAeG 2,400 Fg/F 2 iv :s 46 3AK <HGMBGNHNs BG?NsBHG, KeIe:Me= q 2 PD; Fcrc, FeM:sM:MB< <HEHKe<M:E <:G<eK; mt, FNM:GM MRIe; wt, PBE= MRIe. : iGMeGM MH MKe:M IHINE:MBHG. ; ceMNxBF:; 400 Fg/F 2 iv =1, MAeG 250 Fg/F 2 iv q PD. Background (cont.) 20 Con7erence Proceed:ngs: Colorectal Cancer rESultS E7fcacJ Outcome ITT Population KRAS WT Population KRAS MT Population Cetuximab + FOLFIRI (n=599) FOLFIRI (n=599) Cetuximab + FOLFIRI (n=172) FOLFIRI (n=176) Cetuximab + FOLFIRI (n=105) FOLFIRI (n=87) me=B:G pFS, FH 8.9 8 9.9 8.7 7.6 8.1 h:z:K= K:MBH .85 .68 1.07 P O:ENe .048 .017 .47 orr, % 46.9 38.7 59.3 43.2 36.2 40.2 95% ci 42.9 351 34.8 346.9 51.6 366.7 35.8 350.9 27 346.2 29.9 351.3 P O:ENe .0038 .0025 .46 Median PFS is: " Comparable between ITT and combined WT and MT KRAS populations =or patients receiving cetuximab + FOLFIRI (8.9 vs 9.2 mo) and FOLFIRI (8 vs 8.7 mo). " Signi)cantly longer in KRAS WT than in KRAS MT populations =or patients receiving cetuximab + FOLFIRI (9.9 vs 7.6 mo; hazard ratio, .63; P =.007). " Equivalent in KRAS WT and in KRAS MT populations =or patients receiving FOLFIRI (8.1 vs 8.7 mo; hazard ratio, .97; P =.87) The duration o= treatment with irinotecan was longer in the KRAS WT than the KRAS MT group =or patients receiving FOLFIRI with (32 vs 26 wk) or without (30 vs 24 wk) cetuximab. The longer treatment duration observed in patients receiving cetuximab compared with those receiving no cetuximab correlates with the increased PFS and bene t o= cetuximab + FOLFIRI in KRAS WT patients. Tox:c:tJ Grades 3 and 4 toxicities were similar between KRAS WT and KRAS MT populations, except =or increased neutropenia (25.4% vs 21.9%) and diarrhea (17.3% vs 13.3%) in cetuximab + FOLFIRI group; less febrile neutropenia (0.6% vs 3.8%) and fatigue (2.3% vs 9.5%) was reported =or KRAS WT in this group. concluSionS " Addition of cetuximab to FOLFIRI in mCRC patients increases PFS. " Median PFS and ORR increases in patients with KRAS WT tumors who receive cetuximab + FOLFIRI, compared with those treated with FOLFIRI alone. " mCRC patients with KRAS MT tumors do not bene)t =rom the addition o= cetuximab to FOLFIRI. " KRAS testing should be routinely performed in mCRC patients being considered =or EGFR inhibitor (cetuximab or panitumumab) therapy. rEFErEncES 1 lBéOKe a, b:<AeM jb, bBHge v, eM :E. kraS FNM:MBHGs :s :G BG=eIeG=eGM IKHgGHsMB< ?:<MHK BG I:MBeGMs PBMA :=O:G<e= <HEHKe<M:E <:G<eK MKe:Me= PBMA <eMNxBF:;. J Clin Oncol. 2008;26:374 3379. 2 beGOeGNMB S, S:KMHKe 3bB:G<AB a, dB nB<HE:GMHGBH F, eM :E. oG<HgeGB< :<MBO:MBHG H? MAe raS/raF sBgG:EBGg I:MAP:R BFI:BKs MAe KesIHGse H? FeM:sM:MB< <HEHKe<M:E <:G<eKs MH :GMB 3eIB=eKF:E gKHPMA ?:<MHK Ke<eIMHK :GMB;H=R MAeK:IBes. Cancer Res . 2007;67:2643 32648. 3 de rHH<D w, pBesseO:Nx h, de S<ANMMeK j, eM :E. kraS PBE= 3MRIe sM:Me IKe=B<Ms sNKOBO:E :G= Bs :ssH<B:Me= MH e:KER K:=BHEHgB<:E KesIHGse BG FeM:sM:MB< <HEHKe<M:E <:G<eK MKe:Me= PBMA <eMNxBF:;. Ann Oncol . 2008;19:508 3515. 4 FBGH<<AB:KH G, c:IINzzH F, jäGGe pa, eM :E. EGFr, hEr 32 :G= kraS :s IKe=B<MBOe ?:<MHKs ?HK <eMNxBF:; seGsBMBOBMR BG <HEHKe<M:E <:G<eK. J Clin Oncol. 2007;25(sNIIE, IM 1):168s. a;sMK:<M 4021. 5 dB FBHKe F, bE:G<A:K= F, cA:K;HGGBeK F, eM :E. cEBGB<:E KeEeO:G<e H? kraS FNM:MBHG =eMe<MBHG BG FeM:sM:MB< <HEHKe<M:E <:G<eK MKe:Me= ;R <eMNxBF:; IENs <AeFHMAeK:IR. Br J Cancer . 2007;96:1166 31169. 6 kA:F;:M: 3FHK= S, G:KKeMM cr, meKHIHE nj, eM :E. ExIKessBHG H? eIBKegNEBG :G= :FIABKegNEBG :G= k 3K:s FNM:MBHG sM:MNs IKe=B<M =Bse:se <HGMKHE BG FeM:sM:MB< <HEHKe<M:E <:G<eK I:MBeGMs MKe:Me= PBMA <eMNxBF:;. J Clin Oncol. 2007;25:3230 33237. 7 aF:=H rG, wHE? m, peeMeKs m, eM :E. wBE= 3MRIe kraS Bs KeqNBKe= ?HK I:GBMNFNF:; e? <:<R BG I:MBeGMs PBMA FeM:sM:MB< <HEHKe<M:E <:G<eK. J Clin Oncol. 2008;26:1626 31634. 8 bHDeFeReK c, bHG=:KeGDH i, h:KMF:GG jt, eM :E. kraS sM:MNs :G= e? <:<R H? KsM 3EBGe MKe:MFeGM H? I:MBeGMs PBMA FeM:sM:MB< <HEHKe<M:E <:G<eK (Fcrc) PBMA FolFoX PBMA HK PBMAHNM <eMNxBF:;: MAe opuS exIeKBeG<e. J Clin Oncol. 2008;26(sNIIE, IM 1):178s. a;sMK:<M 4000. ci, <HG =eG<e BGMeKO:E; itt, BGMeGM 3MH 3MKe:M; mt, FNM:GM MRIe; orr, HOeK:EE KesIHGse K:Me; pFS, IKHgKessBHG ?Kee sNKOBO:E; wt, PBE= MRIe. 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 21 Sargent DJ, Marson: S, Th:bodeau SN, et al. Confrmat:on o7 defc:ent m:smatch repa:r (dMMR) as a pred:ct:Ge marker 7or lack o7 beneft 7rom 5 3FU based chemotherapJ :n stage ii and iii colon cancer (CC): a pooled molecular reanalJs:s o7 random:zed chemotherapJ tr:als. J Clin Oncol. 2008;26(suppl, pt 1):180s. Abstract 4008. backGround Fluorourac:l 3based chemotherapJ reg:mens as adjuGant treatment o7 colorectal cancer " Stage III 4FOLFOX is standard of care (based on MOSAIC trial results). 1 " Stage II 4MOSAIC trial showed no bene)t with FOLFOX =or patients with stage II colorectal cancer (CRC). 2 However, the QUASAR group demonstrated an absolute increase in survival of 3.6% with fuorouracil/leucovorin with or without levamisole, compared with observation, indicating a need =or predictive tests to determine which stage II CRC patients will respond to fuorouracil regimens. 3 De7ect:Ge m:smatch repa:r (dMMR) :n CRC " Characteristics include microsatellite instability (MSI) and loss o= expression o= DNA mismatch repair proteins MLH1, MSH2, MSH6, or PMS2. 4 " Defective mismatched repair is implicated in approximately 15% of sporadic CRCs, with > 90% experiencing a loss o= MLH1 expression. " Tumors exhibit poor differentiation, in)ltration of lymphocytes, and signet 3ring cells. Unlike microsatellite stable tumors, which are typically composed o= aneuploid cells, these tumors primarily consist o= diploid cells. 5 " Defective mismatch repair occurs more commonly in =emale patients, early 3stage CRCs, and CRCs that arise near the splenic fexure. 5 " CRCs with high 3frequency MSI (MSI 3H) are resistant to fuorouracil, but have a survival advantage compared to CRCs with microsatellite stable tumors (MSS). Retrospect:Ge tumor samples bJ R:b:c and colleagues 5 " Patients who did not receive chemotherapy, and whose tumors exhibited MSI 3H had a signi cantly longer overall survival (OS) (data censored at 8 yr) than patients whose tumors exhibited low 3=requency MSI (MSI 3L) or MSS (hazard ratio [HR] =or death, .31; 95% con)dence interval [CI], .14 3.72; P =.004). " No bene)t of treatment with adjuvant +uorouracil compared with no adjuvant chemotherapy in patients whose tumors exhibited MSI 3H (HR =or death, 2.17; 95% CI, .84 35.55; P =.1) (data censored at 8 yr) StudJ Object:Ge : con rm dMMR as a predictive marker =or lack o= bene t with fuorouracil therapy in stage II and III CRC. Study dESiGn Retrospective analysis o= tumor samples =rom 5 clinical trials o= stage II or III CRC patients, which compared patients treated with fuorouracil plus levamisole or leucovorin (treated group) with patients not receiving treatment (untreated control group) " MMR is determined by MSI testing or immunohistochemistry (IHC). " De)cient mismatch repair is de)ned as MSI 3H, or loss o= MLH1 or MSH2 protein expression. " Pro)cient mismatch repair is de)ned as MSS or MSI 3L, or by normal MLH1 or MSH2 protein expression. Pr:marJ endpo:nt : determine the e==ect o= MMR status on disease-=ree survival (DFS) =or fuorouracil 3treated patients, with =ocus on stage II patients, =or whom fuorouracil is considered standard therapy. 22 Study charactEriSticS Trial Treatment No. o8 Patients Stage II, % o8 Patients dMMR, % o8 Patients FFcd 8802 FENHKHNK:<BE/leN<HOHKBG 153 66 18 Givio Sitac 301 FENHKHNK:<BE/leN<HOHKBG 183 52 16 ncctG 874651 FENHKHNK:<BE/leN<HOHKBG 32 16 13 G:sMKHBGMesMBG:E iGMeKgKHNI tKB:E 0035 H? MAe nci FENHKHNK:<BE/leO:FBsHEe 72 44 11 ncctG 784852 FENHKHNK:<BE/leO:FBsHEe 51 18 10 Total 491 49 15 =mmr, =e?e<MBOe FBsF:M<A KeI:BK; FFcd, FHG=:MBHG FK:Gç:Bse =e c:G<éKHEHgBe dBgesMBOe; Givio, GKNIIH iGMeKOeGMB oG<HEHgB:; ncctc , nHKMA ceGMK:E c:G<eK tKe:MFeGM GKHNI; nci, n:MBHG:E c:G<eK iGsMBMNMe. Pooled Data Trial Treatment No. o8 Patients Stage II, % o8 Patients dMMR, % o8 Patients FFcd 8802 FENHKHNK:<BE/leN<HOHKBG 154 66 19 Givio Sitac 301 FENHKHNK:<BE/leN<HOHKBG 183 52 16 ncctG 874651 FENHKHNK:<BE/leN<HOHKBG 66 19 12 ncic 3ctG c 303 FENHKHNK:<BE/leN<HOHKBG 292 61 15 G:sMKHBGMesMBG:E iGMeKgKHNI tKB:E 0035 H? MAe nci FENHKHNK:<BE/leO:FBsHEe 215 50 18 ncctG 784852 FENHKHNK:<BE/leO:FBsHEe 117 30 14 Total 1,027 52 16 =mmr, =e?e<MBOe FBsF:M<A KeI:BK; FFcd, FHNG=:MBHG FK:Gç:Bse =e c:G<éKHEHgBe dBgesMBOe; Givio, GKNIIH iGMeKOeGMB oG<HEHgB:; ncct c, nHKMA ceGMK:E c:G<eK tKe:MFeGM GKHNI; nci, n:MBHG:E c:G<eK iGsMBMNMe; ncic, n:MBHG:E c:G<eK iGsMBMNMe H? c:G:=:. rESultS MMR Status Stage II Stage III 5 3FU Untreated 5 3FU Treated 5 3FU Untreated 5 3FU Treated 5 3RK dFS, =mmr, % : 87 79 48 67 hr (95% ci) 3.6 (.6 320.2) .84 (.2 33.6) P O:ENe .15 .81 5 3RK dFS, Immr, % ; 74 73 41 61 hr (95% ci) 1.05 (.58 31.88) .55 (.37 3.82) P O:ENe .88 .003 ci, <HG =eG<e BGMeKO:E; dFS, =Bse:se ?Kee sNKOBO:E; =mmr, =e <BeGM FBsF:M<A KeI:BK; 5-Fu, fNHKHNK:<BE; hr, A:z:K= K:MBH; mmr, F BsF:M<A KeI:BK; Immr, IKH <BeGM FBsF:M<A KeI:BK. : tHM:E H? 47 sM:ge ii :G= 27 sM:ge iii I:MBeGMs. ; tHM:E H? 196 sM:ge ii :G= 221 sM:ge iii I:MBeGMs. Findings con rm results =rom Ribic et al study 5 " Fluorouracil therapy has no bene)cial effect on 5 3year DFS in stages II or III dMMR patients. " Fluorouracil therapy signi)cantly increases 5 3year DFS in stage III pro)cient mismatch repair (pMMR) patients. " Consistency between this, and Ribic )ndings, justi)es pooling the 2 datasets. Con7erence Proceed:ngs: Colorectal Cancer 2008 aFeKB<:G SH<BeMR H? cEBGB<:E oG<HEHgR aGGN:E meeMBGg 23 concluSionS " In untreated stage II CRC patients, dMMR has been validated as a prognostic marker. " In stage II CRC patients with dMMR, +uorouracil therapy (compared with no treatment regimen) may decrease 5 3year DFS and OS. " Untreated stage II CRC patients being considered for fuorouracil therapy should be tested =or MMR status by either MSI or IHC. " This study is limited by age of the studies included, scarce tissue resources =rom original trials, and small sample sizes. " In stage III CRC patients, FOLFOX has replaced fuorouracil/leucovorin therapy. Results o= this study do not apply to patients being evaluated =or FOLFOX therapy; addition o= oxaliplatin to fuorouracil may reverse fuorouracil resistance in dMMR patients. rEFErEncES 1 aG=Ké t, bHGB c, mHNG=eCB 3bHN=B:? l, eM :E. ox:EBIE:MBG, fNHKHNK:<BE, :G= EeN<HOHKBG :s :=CNO:GM MKe:MFeGM ?HK <HEHG <:G<eK. N Engl J Med . 2004;350: 2343 32351. 2 =e GK:FHGM a, bHGB c, n:O:KKH m, eM :E. ox:EBIE:MBG/5Fu/lv BG :=CNO:GM <HEHG <:G<eK: NI=:Me= e? <:<R KesNEMs H? MAe moSaic MKB:E, BG<EN=BGg sNKOBO:E, PBMA : Fe=B:G ?HEEHP 3NI H? sBx Re:Ks. J Clin Oncol. 2007;25(sNIIE, IM1):165s. a;sMK:<M 4007. 3 GK:R r, b:KGPeEE j, m<cHGDeR c, hBEEs rk, wBEEB:Fs nS, keKK dj; ?HK QuaSar cHEE:;HK:MBOe GKHNI. a=CNO:GM <AeFHMAeK:IR OeKsNs H;seKO:MBHG BG I:MBeGMs PBMA <HEHKe<M:E <:G<eK: : K:G=HFBse= sMN=R. Lancet . 2007;370:2020 32029. 4 c:KeMAeKs jm, cA:NA:G dp, FBGD d, eM :E. mBsF:M<A KeI:BK IKH <BeG<R :G= BG OBMKH KesIHGse MH 5 3fNHKHNK:<BE. Gastroenterology . 1999;117:123 3131. 5 rB;B< cm, S:KgeGM dj, mHHKe mj, eM :E. tNFHK FB<KHs:MeEEBMe 3BGsM:;BEBMR sM:MNs :s : IKe=B<MHK H? ;eGe M ?KHF fNHKHNK:<BE 3;:se= :=CNO:GM <AeFHMAeK:IR ?HK <HEHG <:G<eK. N Engl J Med . 2003;349:247 3257. Pooled Data MMR Status Stage II Stage III 5 3FU Untreated 5 3FU Treated 5 3FU Untreated 5 3FU Treated 5 3RK dFS, =mmr, % : 87 72 62 67 hr (95% ci) 2.8 (.98 38.97) 1.08 (.44 32.68) P O:ENe .05 .86 5 3RK dFS, Immr, % ; 72 77 41 58 hr (95% ci) .84 (.57 31.24) .64 (.48 3.84) P O:ENe .38 .001 5 3RK oS, =mmr, % < 93 75 nr hr (95% ci) 3.15 (1.07 39.29) P O:ENe .03 ci, <HG =eG<e BGMeKO:E; dFS, =Bse:se ?Kee sNKOBO:E; =mmr, =e <BeGM FBsF:M<A KeI:BK; 5-Fu, fNHKHNK:<BE; hr, A:z:K= K:MBH; mmr, F BsF:M<A KeI:BK; nr, GHM KeIHKMe=; Immr, IKH <BeGM FBsF:M<A KeI:BK; oS, HOeK:EE sNKOBO:E. : tHM:E H? 102 sM:ge ii :G= 63 sM:ge iii I:MBeGMs. ; tHM:E H? 428 sM:ge ii :G= 434 sM:ge iii I:MBeGMs. < tHM:E H? 55 NGMKe:Me= :G= 47 MKe:Me= I:MBeGMs. " In the pooled data population, 5 3year DFS is signi)cantly greater among untreated patients with dMMR than for the pMMR group (HR, .51; 95% CI, .29 3.89; P =.009). No signi cant di==erence is evident in 5 3year DFS =or treated patients, regardless of dMMR or pMMR status (HR, .79; 95% CI, .49 31.25; P =.3). " For patients with dMMR, +uorouracil therapy signi)cantly decreases 5 3year DFS in stage II; no difference in 5 3year DFS in stage III patients treated with fuorouracil. " For patients with pMMR, +uorouracil therapy signi)cantly increases 5 3year DFS in stage III, but does not bene)t stage II. " Fluorouracil therapy signi)cantly decreases 5 3year OS in stage II patients with dMMR. 24 backGround Oxal:plat:n 3:nduced neurotox:c:tJ " Peripheral sensory neuropathy is a dose 3limiting toxicity. " Etiology: oxalate, a metabolite of oxaliplatin, is a chelator o= =ree calcium and may impair neuron sodium channels. " Acute neurotoxicity is characterized by transient cold hypersensitivity and muscle contractions. " Chronic neurotoxicity is cumulative, but reversible, and correlates with cumulative oxaliplatin dose (> 650 mg/m 2 ). " Retrospective review indicates that administration of calcium and magnesium salts reduces oxaliplatin 3 induced peripheral sensory neuropathy (PSN). 1 StudJ Object:Ge : prospectively evaluate the neuroprotection o= calcium 3 gluconate and magnesium sul=ate (CaMg) administration =or the development o= chronic PSN, grade 2 or greater. N:kceG:ch DA, GrotheJ A, Sloan JA, et al. E77ect o7 :ntraGenous calc:um and magnes:um (iv CaMg) on oxal:plat:n 3:nduced sensorJ neurotox:c:tJ (sNT) :n adjuGant colon cancer: results o7 the phase iii placebo 3controlled, double 3bl:nd NCCTG tr:al N04C7. J Clin Oncol. 2008;26(suppl, pt1):180s. Abstract 4009. Study dESiGn Prospective, placebo 3controlled, randomized, phase 3 trial El:g:b:l:tJ " Adults with colon adenocarcinoma, stages II or III; no evidence o= residual disease a=ter resection " Scheduled to receive 12 cycles of oxaliplatin 3 based (85 mg/m 2 q 2 wk) adjuvant chemotherapy (modi ed FOLFOX6 or FOLFOX4) " No preexisting peripheral neuropathy of any grade, hypercalcemia, history o= atrioventricular block, or administration o= digitalis medication Pr:marJ endpo:nt : assess percentage o= patients with e grade 2 chronic PSN during, or at the end o= therapy, using the National Cancer Institute 3 Common Terminology Criteria =or Adverse Events (NCI-CTCAE), v 3.0. Selected secondarJ endpo:nts " Time to onset and duration of grade e 2 PSN " Quality of life (QOL) parameters Con7erence Proceed:ngs: Colorectal Cancer Neurotoxicity assessed 3 di==erent ways: Grade NCI 3CTCAE v 3.0 Oxaliplatin 3 Speci c Scale Patient 3Reported Outcomes QNesMBHG: dH RHN A:Oe IKH;EeFs PKBMBGg? 1 lHss H? =eeI MeG=HG Kefexes HK I:KesMAesB:, BG<EN=BGg MBGgEBGg, ;NM GHM BGMeK?eKBGg PBMA ?NG<MBHG SeGsHKR sRFIMHFs H? sAHKM =NK:MBHG cnH, i FBgAM ?eeE sHFe MBGgEBGg BG FR

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