Breast : ASCO Abstracts for Review

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1 Breast : ASCO 2011 Susana Campos, MD, MPH Dana Farber Cancer Institute Abstracts for Review Prevention Neoadjuvant Metastatic Brain mets LBA 504: Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP-3 A randomized placebocontrolled clinical trial. LBA 1003: NCIC-CTG MA.20: An Intergroup trial of regional nodal irradiation in early breast cancer. LBA 1005: The effect on pcr of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. Abstract 1006: Neoadjuvant bevacizumab and anthracycline-taxanebased chemotherapy in 686 triple-negative primary beast cancer: Secondary endpoint analysis of the GEPARQUINTO study.. Abstract 505: TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2- overexpressing breast cancer. Abstract 507: Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial) Abstract 1007: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer Abstract 1010: Impact of bevacizumab on efficacy of second line chemotherapy for TNBC: Analysis of Ribbon 2 Abstract 509: LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2- positive metastatic breast cancer before whole brain radiotherapy. 1

2 Prevention Results of NCIC CTG MAP.3 (Excel) Postmenopausal women at increased Risk for breast cancer Stratification o ASA o Gail Score Exemestane 25 mg 5 years Placebo 5 years Goss, et al : Abstract LBA 504 2

3 Primary Objectives of the Trial Incidence of Invasive Breast Cancer Secondary Reduction of pre invasive lesions ( DCIS) Reduction of precursor lesions ( ADH,LCIS) Side effect profile Quality of Life Baseline Characteristics Characteristic Exemestane N=2285 Placebo N=2275 Age,median BMI,median Gail score,median >60 years 1114 (48.8%) 1126 (49.5%) GS>1.66% 929 (40.7%) 905 (39.8) ADH,ALH,LCIS 185 (8.1%) 188 (8.3%) DCIS ( mastectomy) 56 (2.5%) 56 (2.5%) 3

4 Cumulative Incidence of Invasive Breast Cancer Incidence of Invasive and Pre Invasive Breast Events Type of events Invasive + Noninvasive Exemestane Events Annual IR % Placebo Events Annual IR % Hazard Ratio (95%)CI 0.47 (0.27,0.79) P value DCIS % % 0.65 (0.28, 1.51) 0.31 LCIS,ADH ALH events % %.36 (0.11,1.12)

5 Serious Adverse Effects Serious Toxicities Exemestane Placebo P- value Cardiovascular Disease Clinical Skeletal fractures Osteoporosis Other cancers Conclusions Exemestane reduced the incidence of breast cancer by 65 % Exemestane reduced the incidence of pre invasive and precursor lesions Serious toxicities over 3 years have not been seen No difference in the quality of life parameters measured to date 5

6 Local Regional NCIC-CTG MA.20 An Intergroup trial of regional nodal irradiation in early breast cancer Whelan et al, ASCO 2011: Abstract 1003 The primary aim of NCIC: MA.20 Is there an improvement in OS in patients that receive RNI + WBI vs. WBI? 6

7 Study Design and Population Methods 7

8 Disease Free Survival 8

9 Locoregional DFS Distant DFS 9

10 Overall Survival Adverse Events Raises the question as to which patient population? 10

11 Neoadjuvant Trials Neoadjuvant Trials Clinical Trials for Review LBA 1005: The effect on pcr of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. Abstract 1006: Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 686 triple-negative primary beast cancer: Secondary endpoint analysis of the GEPARQUINTO study. Abstract 505: TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer. Abstract 507: Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2- positive breast cancer (CHER-LOB trial) Key points when looking at this data Definition of pcr Patient population : HR+, TNBC, Her 2 positive 11

12 pcr defined as : no invasive cancer in the breast ; may have DCIS Bear HD, et al, ASCO 2011 : Abstract

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GBG 44) pcr defined as: no invasive disease and non- invasive

15 Neoadjuvant bevacizumab an anthracycline- taxane based chemotherapy in 686 TNBC: Secondary Endpoint analysis of the GeparQuinto study ( GBG 44) pcr defined as: no invasive disease and non- invasive residuals in breast and in the nodes Gerber B, et al, ASCO 2011: Abstract

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17 TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer. Chang et al, ASCO 2011 Abstract

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19 pcr defined as :No invasive disease in the breast Reference 19

Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both CHER-LOB trial Abstract 2007 Guarneri V et al C O R E B I O P S Y

20 Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both CHER-LOB trial Abstract 2007 Guarneri V et al C O R E B I O P S Y HER2+ operable breast cancer R A N D O M I Z A T I O N A B C Lapatinib 1500 mg continuous daily dose (CDD) Lapatinib 1000 mg CDD S U R G E R Y Paclitaxel 80 mg/m 2 q. 1 week 5 FU 600 mg/m 2 Epi 75 mg/m 2 CTX 600 mg/m 2 q. 3 weeks Trastuzumab 4 mg/kg loading dose 2 mg/kg q. 1 week LVEF 20

21 pcr Rates with neoadjuvant anti-her2 therapies T L T+L T L T+L T L T+L T L T+L neoaltto CHER-LOB USON GQuinto TBC6 Pac Pac FEC FEC Pac EC Doc Rates of pcr in HER2+ Tumors by Hormone-receptor Status ER+ ER - T L T+L T L T+L T L T+L T L T+L neoaltto CHER-LOB USON GQuinto TBC6 21

Prognostic impact of pcr in patients treated with CT+Trastuzumab in GeparQuattro & Techno HER2+ / ER/PgR

0001 N=200 without pcr rtion disease-free Prpopr P=0.

1028 German meta-analysis: Prognosis of patients without / with pcr by subtype pcr is a surrogate for

22 Prognostic impact of pcr in patients treated with CT+Trastuzumab in GeparQuattro & Techno HER2+ / ER/PgR N=298 HER2+ / ER/PgR + N=356 N=98 with pcr N=79 with pcr Prpop prtion disease-free P< N=200 without pcr rtion disease-free Prpopr P=0.543 N=277 without pcr months months von Minckwitz G et al, ASCO 2011 Abst German meta-analysis: Prognosis of patients without / with pcr by subtype pcr is a surrogate for survival only in groups with a known inferior prognosis: Luminal B(HER2-),HER2+(non-luminal), TNBC pcr is not a surrogate for survival in Luminal A or Luminal B/HER2+ patients given the follow-up of less than 5 years 22

23 Metastatic Disease A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer Iniparib in TN Breast Cancer: Study Design: Multi-center, randomized open-label Phase III Trial Schema N = 519 Study Population: Stage IV TNBC ECOG PS 0 1 Stable CNS metastases allowed 0-2 prior chemotherapies for mtnbc Randomization stratified by prior chemo in the metastatic setting: 1 st -line (no prior therapy) 2 nd /3 rd -line (1-2 prior therapies) R Gem/Carbo (GC) (N= 258) Gemcitabine 1000 mg/m 2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8 21-day cycles Gem/Carbo + Iniparib (GCI) (N= 261) Gemcitabine mg/m2 IV d 1, 8 Carboplatin - AUC2 IV d 1, 8 Iniparib mg/kg IV d 1,4,8,11 Crossover allowed to GCI following Disease Progression* (central review) 21-day cycles *Prospective central radiology review of progression required prior to crossover 96% (n=152) of progressing patients crossed over to GCI at time of primary analysis O Shaughnessy JO, et al, ASCO 2011: Abstract 1007 NCT

24 Efficacy Endpoints ITT population obability of Progression Free Survival Pro PFS GC GCI (N=258) (N=261) Median PFS, mos (95% CI) 4.1 (3.1, 4.6) 5.1 (4.2, 5.8) HR (95% CI) 0.79 (0.65, 0.98) p-value Pre-specified alpha = 0.01 Probability of Survival OS Median OS, mos (95% CI) GC (N=258) 11.1 (9.2, 12.1) GCI (N=261) 11.8 (10.6, 12.9) HR (95% CI) 0.88 (0.69, 1.12) p-value 0.28 Pre-specified alpha = Months Since Study Entry No. at risk GC GCI Months No. at risk GC 25 8 GCI Overall Response Rate* ITT Population Response, n (%) GC N = 258 GCI N = 261 Complete response 4(1 (1.6) 5(1 (1.9) Partial response 74(29) 83 (32) Stable disease 89 (35) 99 (38) Progressive disease 62 (24) 62 (24) Inevaluable RR: 29 (11) 12 (4.6) SD > 6 months 14 (5.4) 19 (7.3) c/w 32% vs 52% in randomized phase II ORR, n (%) 78 (30) 88 (34) (95% CI) (2536%) (2840%) Clinical Benefit Rate, n (%) [CR +PR +SD(> 6 mos)] 92 (36) 107 (41) * Independent central review, RECIST confirmation of response 48 24

25 Exploratory Analysis 2 nd /3 rd -line ITT Population 2 nd / 3 rd -line = 43% patients (222/519) PFS OS 1.0 GCI 42mos( (3.8, 57) 5.7) 1.0 GCI 10.8 mos (9.7,13.1) 0.9 GC 2.9 mos (1.9, 4.1 ) 0.9 GC 8.1 mos (6.6, 10) 0.8 HR=0.67 (0.5, 0.92); 169 events 0.8 HR=0.65 (0.46, 0.91); 132 events bability of Progression Free Survival Pro Probability of Survival Months No. at risk GC GCI Months Why the difference between phase II and phase III? 25

26 Chemo +/- bevacizumab in 2 nd line MBC RIBBON-2 trial design HER2-negative LR/mBC, one prior line of CT, no prior anti-vegf therapy (n=684) Investigator s choice of chemotherapy Taxane or gemcitabine or capecitabine or vinorelbine 2:1 R BEV + CT PLA + CT Treat to disease progression; crossover after progression permitted Brufsky A, et al: ASCO 2011 Abstract 1010 ER = estrogen receptor; PgR = progesterone receptor; PLA = placebo; R = randomization 26

27 TNBC population: PFS Estimated probability PFS BEV + CT (n=112) PLA + CT (n=47) Events, n (%) 94 (84) 42 (89) Median, months HR a (95% CI) Log-rank test ( ) p= a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) Time (months) No. at risk: BEV + CT Placebo + CT TNBC population: Interim OS Estimated probability OS BEV + CT (n=112) PLA + CT (n=47) Events, n (%) 52 (46) 29 (62) Median, months HR a (95% CI) Log-rank test ( ) p= a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) Time (months) No. at risk: BEV + CT Placebo + CT

Brain Metastasis LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole brain

28 Brain Metastasis LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole brain radiotherapy High Risk of Brain Metastases in Patients with HER2+ MBC Study Incidence Bendell et al, % Clayton et al, % Stemmler et al % Kennecke et al % (ER-) 15% (ER+) 28

29 LANDSCAPE: Lapatinib + Capecitabine for new CNS Metastases Primary Endpoint: CNS volumetric response CNS-OR : 29/43 = 67.4% (95% CI: 52-81) CNS Volumetric change n = 43 (%) 80% Reduction 9 (20.9) 50- <80% Reduction 20 (46.5) 20- <50% Reduction 6 (14) > 0- <20% Reduction 2 (4.7) Progression* 6 (14) NSS improvement : 14/24 = 58.3% (95% CI: ) *2 patients had extra-cns disease progression Extra-CNS RECIST response Extra-CNS-OR : 15/35 = 42.9% (95% CI: 26-61) Extra-CNS RECIST evaluation n = 35 (%) Complete response 1 (2.9) Partial response 14 (40) Stable disease 16 (45.7) Progression 4 (11.4) 7 patients had no extra-cns disease 2 patients had no RECIST evaluable lesions 29

30 Studies of Lapatinib for HER2+ Breast Cancer Brain Metastases: Study Regimen N Prior chemo Prior RT Response criteria Lin et al JCO 2008* Lin et al CCR 2009* Toi et al Br JCancer 2009 Lapatinib 39 64% with >2 T+chemo Lapatinib % with >2 T+chemo Lapatinib 10 >80% with >3 prior regimens CNS ORR TTP/PFS OS 95% RECIST 2.6% 3.0 mo NR 100% 50% vol NSS, steroids, lack of non- CNS PD 6% 2.4 mo 6.4 mo NR RECIST? 2 PR NR NR L: lapatinib C: capecitabine T: trastuzumab *Prospective trial Take home messages Prevention Neoadjuvant Metastatic Brain mets LBA 504: Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP-3 A randomized placebocontrolled clinical trial. LBA 1003: NCIC-CTG MA.20: An Intergroup trial of regional nodal irradiation in early breast cancer. LBA 1005: The effect on pcr of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. Abstract 1006: Neoadjuvant bevacizumab and anthracycline-taxanebased chemotherapy in 686 triple-negative primary beast cancer: Secondary endpoint analysis of the GEPARQUINTO study.. Abstract 505: TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2- overexpressing breast cancer. Abstract 507: Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial) Abstract 1007: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer Abstract 1010: Impact of bevacizumab on efficacy of second line chemotherapy for TNBC: Analysis of Ribbon 2 Abstract 509: LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2- positive metastatic breast cancer before whole brain radiotherapy. 30

Review of adjuvant and neo-adjuvant abstracts from SABCS 2011 January 7 th 2012

Review of adjuvant and neo-adjuvant abstracts from SABCS 2011 January 7 th 2012 Ruth M. O Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory