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
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
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 62.5 62.4 BMI,median 27.9 28.1 Gail score,median 2.3 2.3 >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
Cumulative Incidence of Invasive Breast Cancer Incidence of Invasive and Pre Invasive Breast Events Type of events Invasive + Noninvasive Exemestane Events Annual IR 20 0.35 % Placebo Events Annual IR 44 0.77 % Hazard Ratio (95%)CI 0.47 (0.27,0.79) P value 0.004 DCIS 9 0.16 % 14 0.24 % 0.65 (0.28, 1.51) 0.31 LCIS,ADH ALH events 4 0.07 % 11 0.20 %.36 (0.11,1.12) 0.08 4
Serious Adverse Effects Serious Toxicities Exemestane Placebo P- value Cardiovascular Disease 106 111 0.39 Clinical Skeletal fractures 149 143 0.72 Osteoporosis 37 30 0.39 Other cancers 43 38 0.58 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
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
Study Design and Population Methods 7
Disease Free Survival 8
Locoregional DFS Distant DFS 9
Overall Survival Adverse Events Raises the question as to which patient population? 10
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
pcr defined as : no invasive cancer in the breast ; may have DCIS Bear HD, et al, ASCO 2011 : Abstract 1005 12
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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 1006 15
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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 505 17
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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 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
pcr Rates with neoadjuvant anti-her2 therapies 80 70 60 50 40 30 20 10 0 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 90 80 70 60 50 40 30 20 10 0 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 N=298 HER2+ / ER/PgR + N=356 N=98 with pcr N=79 with pcr Prpop prtion disease-free P<0.0001 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. 1028 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
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 - 1000 mg/m2 IV d 1, 8 Carboplatin - AUC2 IV d 1, 8 Iniparib - 5.6 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 NCT00938652 23
Efficacy Endpoints ITT population obability of Progression Free Survival Pro 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 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 0.027 Pre-specified alpha = 0.01 Probability of Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 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 = 0.04 0.1 0.1 0 0 2 4 6 8 10 12 14 16 Months Since Study Entry No. at risk GC 25 17 11 63 38 18 6 1 0 8 1 6 GCI 26 18 13 83 53 11 2 0 0 1 7 8 0 0 2 4 6 8 10 12 14 16 Months No. at risk GC 25 8 GCI 26 1 23 9 24 8 21 4 23 0 18 1 20 4 15 1 16 9 99 38 11 0 11 1 52 15 0 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 1.1 + confirmation of response 48 24
Exploratory Analysis 2 nd /3 rd -line ITT Population 2 nd / 3 rd -line = 43% patients (222/519) PFS OS 1.0 GCI 42mos(38 4.2 (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 0.7 0.6 0.5 0.4 03 0.3 Probability of Survival 0.7 0.6 0.5 0.4 03 0.3 0.2 0.2 0.1 0.1 0 0 2 4 6 8 10 12 14 16 Months No. at risk GC 109 61 42 19 9 5 1 0 0 GCI 113 81 59 32 18 4 0 0 0 0 0 2 4 6 8 10 12 14 16 Months 109 96 84 68 54 29 11 2 0 113 107 98 86 70 47 24 9 0 49 Why the difference between phase II and phase III? 25
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
TNBC population: PFS Estimated probability 1.0 0.8 0.6 0.4 PFS BEV + CT (n=112) PLA + CT (n=47) Events, n (%) 94 (84) 42 (89) Median, months 6.0 2.7 HR a (95% CI) Log-rank test 0.494 (0.33 0.74) p=0.0006 a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) 0.2 0 2.7 6.0 0 5 10 15 20 25 Time (months) No. at risk: BEV + CT 112 65 26 8 4 Placebo + CT 47 11 4 2 TNBC population: Interim OS Estimated probability 1.0 0.8 0.6 OS BEV + CT (n=112) PLA + CT (n=47) Events, n (%) 52 (46) 29 (62) Median, months 17.9 12.6 HR a (95% CI) Log-rank test 0.624 (0.39 1.007) p=0.0534 a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) 0.4 0.2 0 12.6 17.9 0 5 10 15 20 25 30 Time (months) No. at risk: BEV + CT 112 92 73 27 14 5 Placebo + CT 47 38 25 14 4 2 1 27
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, 2003 34% Clayton et al, 2004 39% Stemmler et al 2006 31% Kennecke et al 2010 29% (ER-) 15% (ER+) 28
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: 36.6-77.9) *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
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 237 81% 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