Best of San Antonio 2008

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1 Best of San Antonio 2008 Ellie Guardino, MD/PhD Assistant Professor Stanford University BIG 1 98: a randomized double blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor positive breast cancer Mouridsen et al., Abstract 13 1

2 BIG 1 98 BIG 1 98 Worldwide Collaborative Group and International Breast Cancer Study Group (IBCSG) Initially 2 arms ( ) Design Modified to 4 arms ( ) Include crossover analysis T L L T Primary core analysis Is 5 years of Letrozole superior 5 years of Tamoxifen for adjuvant therapy (median follow up 26 months) BIG 1 98 Trial Design 2 ARM Tamoxifen Letrozole N= 1,828 4 ARM Tamoxifen Tamoxifen Letrozole Letrozole N= 6,182 Letrozole Tamoxifen 2

3 BIG 1 98 Summary of Previous Analysis Primary Core Analysis: 5 years of Letrozole was superior to 5 years of Tamoxifen DFS Time to Distant Recurrence NEJM 2005; 353: JCO 2007; 2: SABC 2008 Abstract 13 New Data Monotherapy 10 years from start of trial (5,000 patients) Median follow up of 76 months 619 patients crossed to letrozole when 2005 data was available and patients unblinded Intent to treat and censored data presented DFS (HR=.88; p=.03), OS (HR =.87; p=.08), TDR (HR =.85; p=. 05) in favor of Letrozole Censored data slightly superior to ITT ITT analysis has bias against letrozole because of cross over 3

4 Sequential Therapy versus Letrozole Tamoxifen unblinded and not included in comparison For DFS: Letrozole alone (87.9%), L T (87.4%), or T L (86.2) no statistical difference For OS: Trend favoring favoring Letrozole (HR = 1.13) and TDR (HR = 1.22) (T > L vs. L) but this did not meet statistical significance For BCR: There was trend favoring the Letrozole arm over the T L There was no difference between the Letrozole and L T arms. BIG 1 98 Mouridsen et al., Abstract 13 4

5 BIG 1 98 Conclusions Superior DFS and OS with Letrozole over Tamoxifen Endocrine therapy for early stage breast cancer in postmenopausal women should start with letrozole Patients on Letrozole can be safely switched to Tamoxifen after 2 years Toxicity Cost Aromatase Inhibitors versus Tamoxifen as Adjuvant Therapy for Postmenopausal Women with Estrogen Receptor Positive Breast Cancer: Meta analysis of Randomized Trials of Monotherapy and Switching Strategies Ingle, et al. Abstract 12 5

6 Monotherapy Trials (10, 000 patients and 50, 000 pt yrs) 1. ATAC (Arimidex, Tamoxifen, Alone or in Combination (ATAC) 2. Breast International Group (BIG) 1 98/International Breast Cancer Study Group (IBCSG) Switch trials (>9,000 patients and 33,000 women years) 1. Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 2. German Austrian Breast Cancer Group (GABG)/Arimidex Nolvadex (ARNO) Intergroup Exemestane Study (IES)/BIG Italian Tamoxifen Anastrozole (ITA) Lancet Oncol. 2008;9:45 53 Clin Oncol. 2007;25: Lancet. 2005;366: Lancet. 2007;369: Lancet. 2007;369: J Clin Oncol. 2005;23: Meta Analysis Results Monotherapy AI benefit: Less breast cancer recurrence absolute 2.7% decrease at 5 years, 3.9% at 8 years (RR 15.3% vs 19.2%, relative decrease 23%, p=0.0001) AI shows no difference in mortality (10 vs 10.5%, p=.1) 6

7 Meta Analysis Results Switch Therapy Switch to AI Benefit: Less Breast Cancer Recurrence: Absolute 3.5% decrease in BC recurrence at 6 years (RR 12.6% vs 16.1%, relative decrease 29%, p< ) Mortality Benefit: Absolute 1.6% decrease at 6 years (6.3% vs 8.0%, relative decrease 22%, p=0.02) Risk of distant recurrence using Oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study Dowsett, et al Abstract 53 7

8 21 gene analysis for prediction of risk in AI treated breast cancer 21 gene RS assesses recurrence risk in ER+, early breast cancer Low risk: RS < 18 Intermediate risk: RS High risk: RS > 30 Validated in node negative patients treated with Tamoxifen Current study evaluates the role of 21 gene analysis for predicting risk of recurrence in postmenopausal women with early stage breast cancer treated with an AI (anastrozole) 21 gene analysis for prediction of risk in AI treated breast cancer Study Design Retrospective analysis from ATAC trial (Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group) randomized phase III study with 100 month follow up (Lancet Oncol. 2008;9:45 53) Postmenopausal women with ER+ early stage breast cancer randomized to tamoxifen or anastrazole (or combination) with long term follow up Primary analysis was time to distant recurrence in node negative patients 8

9 RETROSPECTIVE EVALUATION ATAC Trial (100 month follow up) Postmenopausal Women with ER+ Early Breast Cancer Tissue available for 21 gene analysis 872 LN, 306 LN+ Anastrozole (n = 3,125) Tamoxifen (n = 3,116) Primary Analysis: Multivariate analysis, Lymph node negative, endocrine receptor + No adjuvant chemotherapy, Anastrozole or Tamoxifen therapy Secondary Analysis: relationship between RS and Time to distant recurrence In relationship to the nodal status and treantment arm 21 gene analysis for prediction of risk in AI treated breast cancer Results Evaluated the time to distant recurrence in lymph node negative patients In multivariate analysis the tumor size and RS were independent predictors of time to distant recurrence HR for RS adjusted for age, tumor size, grade was 5.25 (p=.001) HR for tumor size was 2.78 (p =.001) Confirmed the predictive data of RS in ER+ early stage breast cancer treated with Tamoxifen Demonstrated that RS is predictive in ER+ postmenopausal patients treated with anastrozole 9

10 Distant Recurrence Free Rate at 9 Yrs Population n Low RS, % Intermediate RS, % High RS, % P Value Lymph node negative <.001 Lymph node positive <.001 Rate of Distant Recurrence at 9 Yrs Population n Low RS, % Intermediate RS, % High RS, % Lymph node negative Tamoxifen Anastrozole Lymph node positive Tamoxifen Anastrozole

11 Lapatinib combined with letrozole vs letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 trial Johnston et al., Abstract 46 EGF30008 Rationale ER and EGFR cross talk Activation of growth factor receptors (EGFR, HER2) is found in association with endocrine resistance Dual targeting is thus a rational approach to overcome endocrine resistance Combination Trastuzumab and Anastrozole had a superior PFS over Anastrozole alone for HER2+ MBC (TanDEM phase III trial 2.4 vs. 4.8 months) Preclinical endocrine resistance models used to demonstrate that lapatinib and tamoxifen may overcome resistance Breast Cancer Res Treat 2006; 100 Abstract 3 11

12 ER and EGFR cross talk Schiff, R. et al. Clin Cancer Res 2004;10: S Copyright 2004 American Association for Cancer Research EGF30008 Study Design Double Blind, placebo controlled, first line phase III trial Patients with ER + and HER2+/ MBC and no prior treatment advanced disease were enrolled to receive either: Letrozole and placebo Letrozole and Lapatinib Statified by disease sites (bone, visceral) and endocrine status (interval since adjuvant tamoxifen therapy; < 6 mo, >6 mo) Primary endpoint PFS in MBC ER+, HER2+ Secondary endpoints PFS in MBC ER+, OS, ORR, CB rate and safety 12

13 In postmenopausal women with ER+, HER2+ there was a 29% benefit in PFS (from 3.0 to 8.2 months, HR=.71, p=.01) and a significant improvement in CBR (29% vs 48%, p=.oo3) and ORR (15% vs. 28%, p=.021) in favor of letrozole and lapatinib combination over letrozole alone. In postmenopausal women with ER+ and HER2 MBC there was no significant benefit to the combination over letrozole alone A planned stepwise Cox proportion analysis suggests that there may be a subset of ER+, HER2 MBC patients that benefit from the combination (tamoxifen exposure was a significant covariate, Tam < 6 months group) What is the Optimal Adjuvant Chemotherapy for Node Positive Breast Cancer Schedule? Combination? Abstract 75 and 77 13

14 Breast Cancer International Research Group (BCIRG) study 005: randomized phase III multicenter trial Eiermann et al. Abstract 77 BCIRG 005 Study Schema T1 3, N+ HER2 Operable BC N = 3298 Doxirubicin (60 mg/m2) + Cyclophosphamide (600 mg/m2) (4 cycles) Docetaxel (100 mg/m2) (4 cycles) Doxirubicin (50 mg/m2) Docetaxel (75 mg/m2) Cyclophosphamide (500 mg/m2) (6 cycles) For TAC, 93.5% of patients received the planned 6 cycles; for AC T, 90.5% received the 8 cycles. Stratification: Number involved lymph nodes, endocrine receptor status, study site Median of 63 months 14

15 BCIRG 005 Primary Endpoint DFS Intent to treat analysis Secondary Endpoint OS Safety BCIRG 005 Results No difference in DFS (78.6% vs 78.9%) No difference in OS (88.9% vs 88.1%) Significantly more febrile neutropenia with TAC (17.9 vs 8.3 %; p<.0001) Significantly more sensory neuropathy T (42.8 vs 27.5 %; p<.0001), myalgia (50.9 vs 35.8 %; p<.0001) with AC T 15

16 NSABP B 30 Swain, et al., Abstract 75 Ganz, et al., Abstract 76 NSABP B 30 Study Design (Phase III) AC (4 cycles) q 3 week T (docetaxel)(4 cycles) 5351 women Lymph Node + randomized AT (docetaxel) (4 cycles) TAC (4 cycles) Swain, et al., Abstract 75 Ganz, et al., Abstract 76 16

17 NSABP B 30 Study Design Primary Endpoint: Comparison of efficacy in 3 treatment groups Secondary Endpoint: Quality of life comparison among the 3 treatment arms and 2) to compare the amenorrhea in premenopausal women by treatment arms and its relationship to QOL, DFS, OS NSABP B 30 Results Median follow up of 73 months OS was superior in the AC T arm compared to TAC (p=. 034), while AT and TAC had no statistically significant difference in OS Superior DFS in the AC T arm compared to TAC x 4 (p=. 006) and AT x 4 (p=.001) DFS was superior in the AC T group compared to TAC and AT in every stratification category 17

18 Secondary Endpoints NSABP B women from B 30 participated in QOL assessment (FACT B a breast cancer specific scale) AC >T associated with the highest frequency of amenorrhea At 6 months the AC T QOL was significantly lower than the other two arms but at 12 months and beyond the results between all three arms were the same Treatment induced amenorrhea for 6 months or more resulted in improved overall survival (HR=.76; p<.038) and disease free survival (HR=.70; p=.00041), regardless of the regimen NSABP B 30 Results Toxicity and Tolerability Febrile neutropenia (22% for AC T and 16% for TAC and 13% for AT). Stomatitis (5% for AC T, 1% for AT, and 2% for TAC) and infection (8% for AC T, 6% for AT, and 6% for TAC) There were a total of 24 treatment related deaths, and 12 of those were in the TAC group. 97% of patients completed treatment in both the AT and TAC groups. In the AC T group, although 99% completed all cycles in the AC portion of the sequential regimen, only 86% completed the T portion. 18

19 Adjuvant Chemotherapy Unanswered Questions Dose Dense therapy vs. TAC x 6 Toxicity Is it length of therapy? Dose dense data does not support this Duration matters in the context of each regimen? Bevacizumab (BV) maintenance therapy significantly delays disease progression (PD) or death compared with placebo (PL) in the AVADO trial (BV + docetaxel [D] vs D + PL in 1st line HER2 negative locally recurrent [LR] or metastatic breast cancer [mbc]) Fumoleau, et al. Abstract

20 AVADO Results Phase III randomized trial of Docetaxel + Placebo vs. Docetaxel + bevacizumab Significantly longer PFS and higher RR with the addition of bevacizumab to Docetaxel Current analysis evaluates PFS and OS in maintenance therapy bevacizumab AVADO Results The addition of bevacizumab to docetaxel significantly improved PFS in patients with locally recurrent or metastatic breast cancer Maintenance bevacizumab delayed disease progression and death compared with placebo maintenance therapy (exploratory analysis) 20

21 Should we treat patients with Her2+ breast tumors < 1 cm with Chemotherapy? Chemotherapy and Trastuzumab? Abstract 701 and 702 Significant increased recurrence rates among breast cancer patients with HER2 positive tumors 1 cm or smaller Rakkhit, et al. Abstract #

22 HER2 tumors <1 cm To treat or not to treat? HER2 positive breast cancer is associated with poor clinical outcomes Adjuvant trastuzumab has shown highly significant clinical benefit in randomized clinical trials in HER2 positive breast cancer (with chemotherapy) The role of trastuzumab (and chemo) in patients with small HER2 positive tumors is debated and not well defined Current study examines the risk of recurrence with T stage 1a, 1b node negative, HER2 positive breast cancer HER2 tumors <1 cm To treat or not to treat? MD Anderson patients diagnosed with T stage 1a, 1b N0M0 breast cancer Tumors 1 cm Patients were excluded if treated with adjuvant chemotherapy or trastuzumab HER2 positive (FISH >2.0 or IHC 3+) Study outcomes: RFS, DRF, Time to recurrence, Time to distant recurrence 22

23 HER2 tumors <1 cm To treat or not to treat? 965 eligible patients 10% HER2 positive (98 patients) Most characteristics were different between HER2+ and HER2 groups Postmenopausal (56% vs 77%) ER+ (61% vs. 86%) Ductal Histology (92% vs 76%) Nuclear grade 3 (73% vs. 25%) HER2 tumors <1 cm To treat or not to treat? 5 year RFS rate significantly lower among HER2 positive vs HER2 negative patients (77.1% vs 93.7%, respectively; P <.0001) HER2 status (2.68), HR status (.41) and Age (.96) were poor prognostic variables in multivariate analysis and statistically significant for increased risk of recurrence Only HER2 associated with DRFS (HR 5.3; p=.0002) as independent variable 350 patients evaluated from European studies and presented for comparison (6% HER2 positive) Similar trends (87.4% vs 97.0%; P =.043) but numbers small Further investigation warranted 23

24 Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumors. Implications for trastuzumab therapy Tovey et al. Abstract 702 Methods Data in 2006 was recorded prospectively in a database. Case notes were consulted where the HER2+ patients had not received trastuzumab, to ascertain the reasons A retrospective cohort of 367, grade 1 or 2, node negative patients diagnosed between (median followup 6.2yrs) was analysed to assess the impact of HER2 status (Herceptest 3+/FISHpos) on survival. 24

25 Results A total of 951 patients in (43.9%) of these were screen detected. 123(12.9%) were HER2+ (117 were EBC) and 59 (50.4%) of the HER2+ EBCs received trastuzumab therapy Of the 58 (49.6%) patients who did not receive trastuzumab, 25 (43%) were patients considered low risk due to small, node negative, low grade tumors Retrospective cohort. The overall hazard ratio for HER2 positivity was 6.78 with 5yr breast cancer specific survival rates of 96% (HER2 neg) and 68% (HER2 pos). The reduction in survival in HER2 positive cases persisted when patients were split into subgroups by ER status, tumor size and age. Neoadjuvant trastuzumab in patients with HER2 positive locally advanced breast cancer: Primary efficacy analysis of the NOAH trial Gianni, et al., Abstract #31 25

26 NOAH Study Neoadjuvant Trastuzumab HER2 + LABC Chemotherapy with AT x 3 paclitaxel x 4 CMF x 4 vs. Chemotherapy and Trastuzumab Median follow up 3 years HER 2 negative control group received chemotherapy alone Approximately 100 patients per group NOAH Trial Results 327 pts were enrolled and randomized patients were balanced for baseline characteristics EFS rate at 3 years was significantly better in the H + CT arm compared with CT alone: 70.1% vs 53.3%, respectively (HR 0.56; P=0.007). Both ORR and pcr were significantly higher in the H + CT arm compared to CT alone: 89% vs 77% for ORR, respectively (P=0.02); 39% vs 20% for pcr, respectively (P=0.002). Similar results for ORR and pcr were observed between the HER2 positive CT alone arm and the HER2 negative arm. Well tolerated with acceptable cardiac safety. 26

27 SABC 2008 Summary and Conclusions Postmenopausal women with hormone receptor positive breast cancer should receive an Aromatase Inhibitor for adjuvant therapy and upfront AI is favored Switch to Tamoxifen after 2 years of AI is safe and equivalent to AI for 5 years (BIG 1 98) Oncotype Dx has utility in Postmenopausal women who will receive an aromatase inhibitor Role in node negative postmenopausal women warrants further studies Lapatinib and Letrozole is safe and effective therapy for ER+, HER2+ MBC AC x 4 T x 4 is equivalent in efficacy to TAC x 6. TAC x 4 and AT x 4 are inferior to AC T SABC 2008 Summary and Conclusions Trastuzumab should be used in addition to chemotherapy as standard adjuvant and neoadjuvant therapy for HER2+ early breast cancer for appropriate risk patients Tumors < 1 cm which are HER2 positive evaluation of risk of therapy is critical for treatment decision, however, the biology of these tumors appears to significantly increase the risk of recurrence despite the very early stage disease 27

28 Newer Agents A phase II study of trastuzumab DM1, a first, in class HER2 antibodydrug conjugate, in patients with HER2+ metastatic breast cancer Vukelja, S. et al. Abstract 33 28

29 Trastuzumab DM1 (T DM1) An antibody drug conjugate (targeted delivery of antimicrotubule agent (DM1) Has demonstrated activity in a Phase I study The maximally tolerated dose (MTD) for T DM1 given IV every 3 wks was 3.6 mg/kg The current study is a Phase II study in HER2+ breast cancer, progressed on trastuzumab containing therapy T DM1 has single agent clinical activity in pts who have progressed on prior HER2 directed therapy (investigator RR 40%) Tolerated with primary toxicity of thrombocytopenia Neratinib (HKI 272), an irreversible pan erbb receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer Burstein, HJ. Et al. Abstract 37 29

30 Neratinib (HKI 272) Irreversibly inhibits the tyrosine kinase receptors, erbb1 (EGFR) and erbb2 (HER2) In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity (breast cancer) Current trial investigates role of HKI 272 in HER2 + metastatic breast cancer: a) with prior HER2 targeted therapy, or b) no prior HER2 therapy All pts received oral doses of 240 mg of neratinib daily The primary endpoint was progression free (PFS) survival rate at 16 weeks Neratinib (HKI 272) Common adverse events were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea Objective response rates of 26% in pts who had prior treatment with trastuzumab 51% in pts who had no prior treatment with trastuzumab 30

31 Triple negative breast cancer: a phase 2, multi center, open label, randomized trial of gemcitabine/ carboplatin (G/C), with or without BSI 201, a PARP inhibitor. O'Shaughnessy, et al Abstract 2120 Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER 2 overexpressing metastatic breast cancer with prior resistance to trastuzumab Fasolo, et al., Abstract #

32 RAD001 Everolimus inhibits the mammalian target of rapamycin (mtor) serine threonine kinase pathway Mediates proliferation and angiogenesis May play role in trastuzumab resistance Current study: everolimus in combination with trastuzumab and vinorelbine in patients with HER2 overexpressing, trastuzumab resistant metastatic breast cancer Preliminary efficacy results show high rates of SD Feasible and well tolerated (neutropenia is primary toxicity) 32