Update of Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

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1 Update of Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Naoto T. Ueno, MD, PhD, FACP Professor of Medicine Executive Director, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic Chief, Section of Translational Breast Cancer Research Department of Breast Medical Oncology TeamOncology Naoto Ueno

2 Challenges Definition of TNBC Best standard of care Heterogenicity of TNBC Novel targets

3 Definition of TNBC East West Variable OR (95%CI) P Clinical Stage 25% 15% 20% 40% North Stage III (reference) Stage II 1.94 ( ) <0.001 ER% (continuous) 0.99 ( ) PR (continuous) ( ) Nuclear grade III (reference) <0.001 <0.001 High ER level as a continuous variable was significantly associated with low pcr rate With use of recursive partitioning and regression trees method, the recommended cut-off value of ER by pcr was 9.5 I/II 0.45 ( ) <0.001 Neoadjuvant regimen A+T (reference) A 0.3 ( ) <0.001 T 0.26 ( ) Early stage HER2- breast cancer with ER% of less than 10% behaves clinically like TNBC in terms of pcr, survival, and lack of benefit from adjuvant hormonal therapy. Defining TNBC as HER2- breast cancer with ER and PR <10% may be more clinically relevant than <1%. Fujii T, Dong W, Shen Y, Ueno NT. ASCO 2016.

pcr% pcr based on molecular subtype of 12 studies 50 45 40

long-term outcome Hazard Ratio pcr vs non-pcr EFS: 0.24 (0.

4 pcr% pcr based on molecular subtype of 12 studies TNBC pcr had a striking effect with long-term outcome Hazard Ratio pcr vs non-pcr EFS: 0.24 ( ) OS: 0.16 ( ) (Cortazar P, et al. Lancet, 2014)

5 RCB index and the long-term outcome pcr RCB-I Proportionoofopatientsosurviving RCB-II RCB-III Days P<.0001 Masuda H, Baggerly K, Symmans F,Ueno NT. Clin Cancer Research, PMID: 239

6 Drug Therapy in TNBC Chemotherapies are the standard approach Anthracycline, Taxane, are they effective? Any targeted therapy? Is platinum use justified? Any other chemotherapy that is effective?

non-tn: 863 (HER2+ 24%) 30 25 Anthr 20 15 10 5

7 pcr% TNBC: Neoadjuvant Anthracycline, Taxane DACC Stage I III N=1,118 TN: 255, non-tn: 863 (HER2+ 24%) Anthr ALL TNBC non-tnbc Liedtke C, et al. J Clin Oncol, 2008

comparison of 24 randomized adjuvant chemotherapy Regimen Random Effects Model HR (95% CI) Regimen Random Effects Model OR (95% CI) Sequential AC-T 1.

8 Takeo Fujii, et al. JAMA Oncology 2015 The most effective Adeuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Network Meta-analysis Network metalanalysis comparison for which there has been no headltolhead comparison of 24 randomized adjuvant chemotherapy Regimen Random Effects Model HR (95% CI) Regimen Random Effects Model OR (95% CI) Sequential AC-T 1.00 Concurrent ACT AC CMF No adjuvant chemotherapy Platinum Regimens TC 0.93 ( ) 1.13 ( ) 1.39 ( ) 1.45 ( ) 0.93 ( ) 0.95 ( ) SequentialoAC-T ConcurrentoACT AC CMF PlatinumoRegimens TC o( ) 0.73o( ) 0.18o( ) 3.55o( ) 0.56o( ) Meta-regression analysis with adjusting for hormone receptor status for overall Overall unacceptable Adverse Events

9 Best Standard of Care FEC 100 Paclitaxel/ Docetaxel Dose dense AC Paclitaxel AC weekly paclitaxel TAC x 6 CEF FEC 100 A/E CMF CAF AC Docetaxel TC AC Paclitaxel FEC 50 FAC CMF AC A+ Docetaxel TAC x 4 Arrows indicated direct comparisons from randomized trials Benefits not drawn to scale TripathyoDo2015

* TNBC: Neoadjuvant Platinum vs Non-platinum Alba E, et al GEMCAM/ 2006-03 (Breast Cancer Res Treat,2012) von Minckwitz G,et al GeparSixto (Lancet Oncol, 2014) Sikov WM, et al CALGB/Alliance 40603 (J

10 * TNBC: Neoadjuvant Platinum vs Non-platinum Alba E, et al GEMCAM/ (Breast Cancer Res Treat,2012) von Minckwitz G,et al GeparSixto (Lancet Oncol, 2014) Sikov WM, et al CALGB/Alliance (J Clin Oncol,2015) CK5/6 or EGFR+ (N=94) TN or HER2+ (TN: N=315) TN cstage II-III (N=443) EC DTX EC CBDCA(q3w)/DTX Lip-DOX/PTX + Bmab Lip-DOX/PTX/CBDCA(qd) + Bmab PTX dd-ac PTX/CBDCA(q3w) dd-ac PTX CEF * * Ando M, et al (Breast Cancer Res Treat, 2014) HER2- cstage II/IIIA (N=179) PTX/CBDCA(q3w) CEF * * p< pcr%

DTX/GEM AC+Bmab (N=1,206) TNBC: 40% HER2- (N=1,925) TNBC (N=443) EC DTX EC DTX + Bmab TNBC:N=663 PTXRCBDCA(q3w) dd-ac

11 Neoadjuvant Role of Bevacizumab Bear H, et al NSABP B-40 (N Engl J Med, 2010) von Minckwitz G, et al GeparQuinto study (N Engl J Med, 2012) Sikov WM, et al CALGB/Alliance (J Clin Oncol,2015) DTX or DTX/CAPE or DTX/GEM AC HER2- DTX or DTX/CAPE or DTX/GEM AC+Bmab (N=1,206) TNBC: 40% HER2- (N=1,925) TNBC (N=443) EC DTX EC DTX + Bmab TNBC:N=663 PTXRCBDCA(q3w) dd-ac PTXRCBDCA(q3w) dd-ac + Bmab * * Earl H, et al ARTemis (J Clin Oncol,2015) DTX CEF HER2- DTX CEF + Bmab * (N=800) TNBC: N=241 *p<0.05 * pcr%

TNBC and basalllike breast cancer TNBC butonotobasal 10-30% Can also include claudin-low, a subtype notable for high expression of stem cell markers IHC

12 TNBC and basalllike breast cancer TNBC butonotobasal 10-30% Can also include claudin-low, a subtype notable for high expression of stem cell markers IHC TNBC & Basal-like Array BasalobutonotoTNBC 15-40% are ER+, PR+, or HER2+o Highograde ER- PRo- HER- HigoKi-67 p53mut CK14 p63 Prat A, et al, The Oncologist, 2013

13 TNBC is Heterogeneous PratoA,oetoal,oMolecoOncolo2010 PratoA,oetoal,oTheoOncologist,o2013

14 Heterogenicity of TNBC TNBC gene signatures Training set Validation set 1. Basal-like subtype 1 (BL1) 2 Basal-like subtype 2 (BL2) Increasedoexpressionoofocellocycleo andodnaodamageoresponseogenes ooo 3. Immunomodulatory (IM) Enrichedoforogeneoontologiesoino immuneocelloprocesses 4. Mesenchymal (M) 5. Mesenchymal stem-like (MSL) Enrichedoforogeneoexpressionoofoo epithelial-mesenchymalotransitiono andogrowthofactoropathways 6. Luminal androgen receptor (LAR) Characterizedobyoandrogeno receptorosignaling 7. Unknown (unstable) Lehmann BD et al. J Clin Invest PMID:o

15 Clonal and mutational evolution spectrum of primary TNBC Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashivili G, Ding, J, Tes K, Haffari G, Bashashati A, et al. Nature PMID

16 Relationship between PAM 50 subtypes and the Vanderbilt 7 subtypes Basal (n = 75) BL1 Non-basal (n = 17) 17% 1% 10% 23% 21% 20% 8% BL2 M IM MSL LAR 35% 6% 59% LAR MS L US Masuda H, Baggerly K, Symmans F, Ueno NT. Clin Cancer Research, PMID:

17 Relationship between RCB index and the 7 subtypes 100,0 Distributiono(%)o 80,0 60,0 40,0 20,0 0,0 BL1 BL2 M IM MSL LAR UNS RCB-III RCB-II RCB-I pcr Proportionoofopatientsosurviving pcr RCB-I RCB-II RCB-III P<.0001 Days 130oTNBCogeneoexpressionomicroarrayso obtainedobetweenomarcho2000oandomarcho 2010oatoMDoAnderson Masuda H, Baggerly K, Symmans F,Ueno NT. Clin Cancer Research, PMID: 239

18 DMFS and OS using 7 subtypes Distant metastasis-free survival Overall survival Proportionoofopatientsosurviving LAR BL2 P=0.371 Proportionoofopatientsosurviving LAR P=0.287 BL2 Days Days Masuda H, Baggerly K, Symmans F,Ueno NT. Clin Cancer Research, PMID: 239

19 Refinement of TNBC molecular subtypes TNBComolecularosubtypesofromo6o(TNBCtype)o intoofouro(tnbctype-4)otumor-specificosubtypeso (BL1,oBL2,oM,oLAR) pcro41%oofobl1,o18%oforobl2oando29%oforolaro witho95%oconfidenceointervalso(cis;o[33,o51],o[9,o 28],o[17,o41],orespectively). MSLoisocancerostromalocells,owhichomayoreflecto theocanceromicroenvironmentooroinadequacyoofo theobiopsy Lehmann et al. PLOS 2016

20 IM TILoinfiltration Immuneocheckpointoregulatoryogeneso CTLA4oCD274o(theogeneoencodingoPD-L1)o andopdcd1o(theogeneoencodingopd-1) LowoinoMoandoAR. ConfinedotooBL1,oBL2,oandoMSL.

21 Summary of TNBC Heterogenicity pcr is an important clinical readout for long-term outcomes Unique gene pathway signatures that determine the prognosis and pcr No clear gene mutation drivers Few targets have been clinically proven

22 Challenges with T/FAC preoperative chemotherapy Addition of active agents in preoperative chemotherapy increases toxicity Patients often opt out of additional chemotherapy after SOC chemotherapy Diagnostic imaging response at 12 weeks (~50-80% accuracy for pcr/rcb-i)

23 Treatment strategy for newly diagnosed primary TNBC Trial Agent AC Chemo-sensitive Paclitaxel PDLl1i EGFRi MPDL3280A Chemo-insensitive (prediction & interim imaging) panitumumab ARi BRCA1/2 + mtori PARPi enzalutamide Vimentino+ AR+ everolimus (mesenchymal) TBD Other (enrichedoforobasal-like) PARPi+o chemo mtorio+o chemo ARio+o chemo EGFRio+o chemo PDL-1io+o chemo *comparison with control predictor unknown group Improvedorateoofo pcr/rcb-i? Single-armophaseoIIotrials pcroimprovement:o5% 20% no=o37 Two-stageodesign;ocloseoifopCR/RCB- Ionotoseenoino>1oofo14opatientso

24 Immunelassociated Mesenchymalllike Basalllike Luminal/Apocrinellike HER2lenriched LeoDuoF,oEckhardtoBL,oLimoB,oLittonoJK,oMoulderoS,oMeric-Bernstam,oGonzalez- AngulooM,oUenooNT.oOncotarget,o2015.

25 Basalllike LeoDuoF,oEckhardtoBL,oLimoB,oLittonoJK,oMoulderoS,oMeric-Bernstam,oGonzalez-AngulooM,oUenooNT.oOncotarget,o2015.

26 Mesenchymalllike LeoDuoF,oEckhardtoBL,oLimoB,oLittonoJK,oMoulderoS,oMeric-Bernstam,oGonzalez-AngulooM,oUenooNT.oOncotarget,o2015.

27 Immune associated LeoDuoF,oEckhardtoBL,oLimoB,oLittonoJK,oMoulderoS,oMeric-Bernstam,oGonzalez-AngulooM,oUenooNT.oOncotarget,o2015.

28 Luminal/Apocrinellike & HER2lenriched LeoDuoF,oEckhardtoBL,oLimoB,oLittonoJK,oMoulderoS,oMeric-Bernstam,oGonzalez-AngulooM,oUenooNT.oOncotarget,o2015.

29 Current Approaches for Neoadjuvant Chemotherapy in TNBC ER < 10% behaves like TNBC Taxane-anthracycline sequential is SOC Standard is to give Anthracycline and Taxane sequential treatment Use of carboplatin and bevacizumab lacks long-term follow up data Use of capecitabine or platinum remains to be unkown for those who achieve non-pcr Clinically pragmatic, molecular discovery-driven, and in-between approaches

30 Acknowledgment Pathology FraseroSymmans MikeoGilcrease AyseguloSahin Surgical Oncology BethoMittendorf AlastairoThompson KellyoHunt DalliahoBlack Diagnostic Imaging RosalindoCandelaria BeatrizoAdrada MiaoRauch WeioYang Radiation Oncology MikeoStauder Biostatistics KenoHess JoeoEnsor Basic Science HelenoPiwnica-Worms SenduraioMani PeteoDavies CliffoStephan Investigational Cancer Therapeutics FundaoMeric-Bernstam Breast Medical Oncology StacyoMoulder JenniferoLitton BanuoArun VicenteoValero BoraoLim RashmioMurthy NaotooT.oUeno Women s Cancer Moonshot Leadership GordonoMills AniloSood Mien-ChieoHung DebuoTripathy Administrative Staff JasonoBooks WalkeroAveritt Research Staff BetsyoWilliams ThorunnoHelgason AlysonoClayborn AksharaoRaghavendra JieoWilley

31 Metastatic TNBC N=111 (stage IV 14%, Neo or Adj 75%) Median Survival 13.3 M Median Chemo Durat 1 st - Line 2 nd - Line 3 rd - Line (Kassam F, et al. Clin Breast Res, 200

32 TNBC に対する薬物療法 Neoadjuvant - Anthracycline と Taxane 併用 : pcr 率向上 - pcr は予後と相関 - Anthracycline, Taxane に bevacizumab 併用長期成績 : pcr 率向上なし - Anthracycline, Taxane に Carboplatin 併用 : pcr 率向上 Adjuvant - Anthracycline に Taxane: DFS, OS 延長 - Dose-dense chemo: OS 延長? Metastatic - Bevacizumab+chemo: PFS 延長

33 TNBC: Metastatic Bevacizumab *p<0.05 E2100 (N=722) (Gray R, et al. JCO,2009) AVADO (N=705) (Miles DW, et al. JCO, 2010) RIBBON-1 (N=1,237) (Robert NJ, et al. JCO, 2011) RIBBON-2 (N=684) (Brufsky A, et al. JCO, 2011) Patient Population Regimen PFS(m) 1 st -line HER2-98% TN (N=232) 1 st -line HER2- TN (N=167) 1 st -line HER2- TN (N=279) 2 nd -line HER2- TN (N=159) wptx + Bmab wptx DTX + Bmab DTX + Placebo T or A + Bmab T or A + Placebo CAPE + Bmab CAPE + Placebo Chemo + Bmab Chemo + Placebo HR 0.49* ( ) HR vs vs vs 2.7* IMELDA (N=185) (Gllgrov J,et al. Lancet Oncol, 2014) 1 st -line DTX+Bamb 奏効 HER2- TN (N=56) CAPE + Bmab Bmab 7.6 vs 3.3 TANIA (N=494) (von Minckzitz G, et al. Lancet Oncol, 1 st -line Chemo+Bmab>3M HER2- Chemo + Bmab Chemo 4.9 vs 2.1*

34 抗 EGFR TNBC: Metastatic 抗体 Cetuximab Target Population Regimen ORR PFS OS Phase 2 1 st or 2 nd line (Baselga J, et al. J Clin Oncol, 2013) Phase 2 1 st or 2 nd line (Lisa A, et al. J Clin Oncol, 2012) Phase 2 1 st line (Tredan O, et al. Clin Breast Res, 2015) EGFR:TNBC 64% で発現 TNBC basal-like2: EGF 遺伝子増幅 (+) CDDP + Cmab CDDP (N=115) 2:1 Cmab Cmab + CBDCA(qw) (N=31) Cmab + CBDCA(qw) (N=71) Cmab + Ixabepilone Ixabepilone (N=79) * (-) (* p<.05)

35 TNBC: Metastatic Platinum vs Non-platinum 比較試験対象 Regimen 奏効率 PFS ( 月 ) Phase 2 1 st -line Prior-Anthra(+) (Fan Y, et al. Ann Oncol, 2013) Phase 3 1 st -line (Hu Xi-Chun, et al. Lancet Oncol, 2015) Phase 3 TNBCorBRCA1/2mt+ 1 st -line Prior-Anthra(+) (Tutt A, et al. SABCS, 2014, abstr#s3-01) DTX + CDDP DTX + Cape (N=53) GEM + CDDP GEM + PTX (N=236) CBDCA DTX (100) (N=376) 63.0%* 15.4% 64%* 49% 31.4% 35.6% Basal-like (N=174) 32.6vs35.2% 10.9* * OS ( 月 ) 32.8 * 21.5 NS * p<0.05

36 TNBC: Metastatic Eribulin EMBRACE と 301 試験の pooled analysis EMBRACE N= 試験 N=1,102 Prior Anth & Taxane Prior 1 for MBC Eriburin vs CAPE, etc. TNBC N=352 PFS: 2.8 vs 2.5ヶ月 (p=0.028) OS: 12.4 vs 8.1ヶ月 (p=0.005) Overall survival (Pivot X, et al. Ann Oncol, 2016 [Epub)

New Treatment Directions for Triple Negative Breast Cancer (TNBC)

New Treatment Directions for Triple Negative Breast Cancer (TNBC) Naoto T. Ueno, MD, PhD, FACP Professor of Medicine Executive Director, Morgan Welch IBC Research Program and Clinic Chief, Section of Translational