Novel&Breast&Cancer&Therapy:& - PowerPoint PPT Presentation

Novel&Breast&Cancer&Therapy:& Should&we&have&any& cardiovascular&concerns? Dr.$Chris)ne$Simmons,$MD$MSc$FRCPC$ Medical$Oncologist,$BCCA$Vancouver$ Clinical$Associate$Professor,$Faculty$of$Medicine,$UBC$ Founder$and$Chair,$All$in$Cancer/Women$in$Cancer$

Disclosures • Honoraria:$Eisai,$Amgen,$Roche,$Novar)s$ $ • Grants:$Roche,$Amgen,$Genomic$Health$ • Research:$Roche,$Amgen,$Novar)s$

Objec?ves 1.$To$summarize$the$main$areas$of$novel$breast$cancer$therapeu)cs$$ • Mechanism$of$ac)on$ • Improvement$in$breast$cancer$outcomes$observed$ 2.$To$review$the$current$knowledge$of$cardioStoxicity$of$novel$breast$ cancer$therapeu)cs$ • What$has$been$demonstrated$ • What$has$been$studied$ • What$has$not$been$studied$ • What$further$poten)al$outcomes$could$we$expect$

Novel&Breast&Cancer&Therapy:& Se@ng&the&Stage • Drug$Development$in$Oncology$ • Inves)ga)onal$new$drugs$are$developed$based$on$poten)al$cyctotoxicity$and$ ini)ally$studied$(usually)$in$cell$lines,$animal$models,$and$then$in$the$ advanced$seWng$ • Phase$I$studies,$“First$in$Human”$studies,$poten)ally$no$further$therapeu)c$op)ons $$ • Phase$II$studies$(single$arm,$advanced$disease)$ • Phase$III$studies$(randomized$controlled$trials,$usually$in$metasta)c$seWng$to$start)$ • Median$Survival$for$metasta)c$breast$cancer$pa)ent$in$2016$ • Typically$about$2S3$years$(ACS,$ASCO)$ • Improved$to$median$of$26$mos$$from$20$mos$(SEER$registry$2007S2011$vs.$ 1988S1991)$ • 5$year$survival$rate$23%,$10$year$survival$rate$5%$

What&does&this&mean? • Metasta)c$seWng$is$where$novel$therapeu)cs$are$developed$typically$ • Collec)ng$long$term$cardioStoxicity$data$collec)on$is$s)ll$a$hard$sell$in$ this$seWng!$ • Cost$of$trials$ • Pa)ent$engagement$ • Pragma)sm$ • SOOOOO…..$ • There$is$s)ll$a$lot$that$we$don’t$know$and$s)ll$a$lot$to$learn$ • Collabora'on)between)oncology)and)cardiology)is)key)in)trial)development)

Novel&strategies&in&ER+&disease

RESTRICTION$POINT$

CDK&4/6&inhibi?on $

Cardiac&Concerns Exclusion$criteria :$ • Clinically$significant,$uncontrolled$heart$disease$and/or$cardiac$repolariza)on$abnormality$ including$any$of$the$following:$ • History$of$myocardial$infarc)on$(MI),$angina$pectoris,$symptoma)c$pericardi)s,$or$coronary$artery$bypass$ graf$(CABG)$within$6$months$prior$to$study$entry$ • Documented$cardiomyopathy$ • Pa)ent$has$a$known$Lef$Ventricular$Frac)on$(LVEF)$<50%$as$determined$by$Mul)ple$Gated$acquisi)on$ (MUGA)$scan$or$echocardiogram$(ECHO).$ • Long$QT$syndrome$or$family$history$of$long$QT$syndrome$or$family$history$of$idiopathic$sudden$death$or$ congenital$long$QT$syndrome,$or$any$of$the$following:$i.$Risk$factors$for$Torsades$de$Pointe$(TdP)$including$ uncorrected$hypokalemia$or$hypomagnesaemia,$history$of$cardiac$failure,$or$history$of$clinically$significant/ symptoma)c$bradycardia$ii.$Concomitant$medica)ons(s)$with$a$known$risk$to$prolong$the$QT$interval$and/or$ known$to$cause$Torsades$de$Pointe$that$cannot$be$discon)nued$or$replaced$by$safe$alterna)ve$medica)on$ (e.g.$within$5$halfSlives$or$7$days$prior$to$star)ng$study$drug)$iii.$Inability$to$determine$the$QTc$interval$ • Clinically$significant$cardiac$arrhythmias$(e.g.,$ventricular$tachycardia),$complete$lef$bundle$branch$block,$ highSgrade$AV$block$(e.g.,$bifascicular$block,$Mobitz$type$II$and$third$degree$AV$block)$ • Corrected$QT$interval$(QTc)$>$480$msec$on$screening$electrocardiogram.$If$QTc$prolonga)on$is$felt$to$be$ related$to$electrolyte$imbalance,$an$EKG$can$be$repeated$afer$correc)on$of$electrolytes.$

BoKom&line • CDK4/6$inhibitors$double$the$progression$free$survival$of$metasta)c$ER +Her2S$breast$cancer$pa)ents$ • Likely$will$show$impressive$OS$benefit$as$data$matures$ • These$agents$are$being$used$more$rou)nely$with$access$via$compassionate$ access$programs$given$the$impressive$results$ • But$these$agents$have$been$associated$with$QTc$prolonga)on,$and$current$ ongoing$studies$exclude$pa)ents$at$risk$for$QTc$prolonga)on$ • ECG$is$NOT$currently$part$of$standard$rou)ne$follow$up$on$metasta)c$ breast$cancer$pa)ents$

Novel&Therapies&in&Her2+&disease

Pertuz+$ Tras$+$ An?MHer2&therapies&in& chemo$ combina?on 50$ Not$so$much$novel,$as$evolved$ First$line$Trastuzumab+Pertuzumab+Taxane$ TDMS1$ now$standard$of$care$ 30.9$ Second$line$TrastuzumabSEmtansine$ 27$ $ 25.5$ 25.1$ When/should/how$do$we$monitor$cardiac$ func)on$in$the$metasta)c$seWng?$ 15.6$ What$are$the$implica)ons$of$compromising$ 12$ curability$in$the$adjuvant$seWng$for$ asymptoma)c$effects$on$LVEF?$ What$are$the$implica)ons$of$survivorship$ management$for$lower$risk$Her2+$disease?$ Slamon$ Glemon$ Baselga$ Geyer$ von$ Verma$ Blackwell$ $ 2001$ 2012$ 2013$ 2006$ Minkwitz$ 2012$ 2010$ 2009$ 3+$line$ Second$line$ First$line$metasta)c$ therapy$ metasta)c$ median$OS$ median$OS$

We&are&ge@ng&beKer…. • Increased$interest$in$studying$agents$with$fewer$poten)al$cardiotoxic$ effects$ • MMS302$is$a$novel,$HER2Stargeted$an)bodySliposomal$doxorubicin$ conjugate$that$specifically$targets$HER2Soverexpressing$cells$ • Preclinical$and$Phase$1$data$suggest$that$MMS302,$as$a$monotherapy$ or$in$combina)on$with$trastuzumab,$could$be$effec)ve$for$managing$ previously$treated,$anthracyclineSnaïve,$HER2Sposi)ve$breast$cancer$ • Would$allow$for$adequate$an)Sneoplas)c$therapy$without$the$ cardiotoxicity$observed$with$free$doxorubicin$formula)on$

Immunotherapy&in&Breast&cancer

Cardiac&concerns&with&immunotherapy • Most$common$side$effects$are$related$to$immunotherapy$ • coli)s,$hepa))s,$rash$and$endocrinopathies$ • myocardial$fibrosis$$ • pericardi)s$$ • cardiomyopathy$with$takotsuboSlike$syndrome$induced$by$ipilimumab$ • acute$heart$failure$under$therapy$with$pembrolizumab$ • Currently$only$case$series$ • Single$agent$effec)ve,$but$likely$will$combine$the$other$therapies$in$ future$ • Cardiotoxicity$poten)ally$underes)mated$

Novel&Therapeu?cs&and&Cardiotoxicity:&& S?ll&a&concern Novel)Area) Poten'al)Cardiac)concerns) ER+$breast$cancer:$ • QTc$prolonga)on$–$could$poten)ally$ • Cell$cycle$inhibi)on$(CDK4/6$ be$severe$when$used$in$general$pop$ inhibitors)$ Her2+$disease$ • Effects$on$myocyte$contrac)lity,$but$ • Mul)San)SHer2$agents$ we’re$geWng$smarter!$ Triple$nega)ve$breast$cancer$ • Poten)al$endocrinopathies$ • Immunotherapy$ • Arrhythmia,$Adrenal$insufficiency,$ Myocardi)s,$Pericardi)s$

Thank&you!