North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Meeting ~ February 26 27, 2010 The Ballantyne Resort ~ Charlotte, NC Breast Cancer: Chemotherapy and Novel Agents Lisa A. Carey, M.D. University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
Faculty Disclosure Consultant: sanofi aventis, BiPar, Wyeth, Pfizer, Genentech, BMS, Novartis Research Support: GSK, Boehringer Ingelheim, Genentech, Wyeth, BMS
NEW DEVELOPMENTS IN CHEMOTHERAPY DECISION MAKING
CAF Benefit in Node positive by Recurrence Score (RS) DFS: RS <18 RS 18 30 RS 31 1.00 0.75 prognostic 0.50 for tamoxifen treated patients with positive nodes and predicts significant benefit of CAF in high recurrence score. A low 0.25 recurrence score identifies women who might not benefit from 0.00 p = 0.97 at 10 years HR 1.02 (0.54 1.93) CAF T (n=91, 26 events) Tamoxifen (n=55, 15 events) p = 0.48 at 10 years HR 0.72 (0.39 1.31) CAF T (n=46, 22 events) Tamoxifen (n=57, 20 events) p = 0.033 at 10 years HR 0.59 (0.35 1.01) anthracycline based chemotherapy, despite positive nodes. CAF T (n=47, 26 events) Tamoxifen (n=71, 28 events) 0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10 No benefit to CAF over time if low RS Years since registration Interaction p=0.053 Strong benefit if high RS 4 Albain KS, et al. Lancet Oncol. 2009. CAF=cyclophosphamide, doxorubicin + fluorouracil
Clinical Applications of Genomic Profiles Depend On: Identification of a low risk group in whom no further therapy is needed OR Confirmation of accurate prediction of response based on profile Have either of those criteria been met for multigene profiles in N+?
Prognostic Profiles Work in HR+ Regardless of Nodal Status. TransATAC 306 of 9366 node positive Endocrine Rx only RS was prognostic in N+: Other prognostic profiles in N+: E2197 (RS, all chemoendocrine) 70 gene profile retrospective study SWOG 8814 (RS) Tam vs CAF Tam Only 1 asks a therapeutic question All (n=1231) Node negative (n=872) Tamoxifen (n=432) Anastrozole (n= 440) Node positive (n=306) Tamoxifen (n=152) Anastrozole (n=154) 0.1 1.0 4.35 10.0 Adjusted HR (for 50 pt change)* (central grading) Dowsett et al. SABCS 08, Abs 53; Goldstein et al, JCO 08, Mook et al, BCRT 2009; Albain et al, Lancet Oncol 09
Genomic Profiles and Absolute Risk: Only Part of the Equation What is the risk of recurrence in N+ postmenopausal women with low Recurrence Score treated with tamoxifen only? SWOG 8814 40% relapse at 10y ATAC 10% relapse at 10y Selection matters
Recurrence Score and Prognosis in Node-positive: SWOG 8814 Tamoxifen-alone Arm RS Group 10-year DFS 10-year OS RS <18 (n=55) 60% 77% RS 18-30 (n=46) 49% 68% RS 31 (n=47) 43% 51% Prognostic, but there is NO good risk group here Albain KS et al. Lancet Oncol. 2009 Dec: Epub ahead of print. 8
Level of Evidence Re Chemo Benefit? I II III IV V Prospective, high power, designed to test marker) OR Meta-analysis of Level II Prospective clinical trial not designed to test marker. Large study, high % of tissue available. Large but retrospective studies OR Small # of specimens Small retrospective studies, casecontrol studies Pilot studies N=1477 All postmenopausal (Relatively small trial) Concurrent CAF/T N=967 N= 367 Missing tissue Int/High RS: not helpful N=146 low Recurrence Score (the group of interest) 9
Recurrence Score and Chemo Benefit at 10 Years Point of inflection RS ~8 B-20 was much higher (benefit not seen until high RS) Effect of concurrent tam? Effect of higher risk = higher benefit? Is there a RS that we know identifies a group with no benefit of chemo, even 3 rd generation? Does this mean that RS=8 is meaningful? This is why there is a TailoRx trial
ECOG 1199 By Race and Tumor Subtype 80 Paclitaxel A C N= 4817 405 (8%) African American 175 mg/m 2 35 Docetaxel 100 Sparano J, et al. N Engl J Med. 2008 Apr 17; 358(16):1663-71.
Race and Outcome in E1199 In E1199 (uniform Rx), black pts had worse DFS and OS than non black. Why? Sparano J, et al. SABCS 2009.
Disease-Free and Overall Survival: Triple Negative Disease No difference within triple negative subtype (n~900, 129 black) Sparano J, et al. SABCS 2009.
Race and Outcome in Hormone Receptor + HER2- Difference driven by ER positive, HER2 negative subsets.? Heterogeneity of non protocol driven endocrine therapy?? Heterogeneity of luminal subtypes by race? Sparano J, et al. SABCS 2009.
Multivariate Model in HR-Pos/HER2-Neg Group: DFS Additional Variables Added to Above Model HR (95% CI) P value Black race only 1.41 (1.00, 2.00) 0.053 Obesity only 1.26 (1.04, 1.51) 0.016 Race & Obesity Race Obesity Race-Obesity Interaction Black (Obese) Black (Not Obese) 1.33 (0.93,1.89) 1.23 (1.02, 1.49) 1.09 (0.68, 1.74) 1.80 (1.06, 3.03) 0.120 0.030 0.720 0.028 Proportional Hazards Model - included Age, Node #, Size, Menopausal Status, Surgery Type. Type of endocrine therapy was excluded because was NS in univariate model. Sparano J, et al. SABCS 2009.
Conclusions Black race associated with Younger age and more obesity at presentation Higher rates of triple negative and HER2-pos disease Larger tumor size and less nodal involvement Poorer outcomes in HR-pos/HER2-neg disease Not explained by comorbidities or disparities in care Obesity also appears to be a contributing factor Other confounding variables Findings consistent with some prior reports Clinical trial populations
NEW DEVELOPMENTS Biologically Unselected Populations
First Line Bevacizumab Trials Miller K et al. New England J Med 2007; 357(26):2666 76; Miles D et al, J Clin Oncol 2008;26:50s, Abstract 1036; Robert N et al. J Clin Oncol 2009; 27:18s:, Abstract 1005.
Summary Results First Line Bevacizumab PFS (primary endpoint) 12 vs. 6 mos (p<0.001) ORR: 37 vs. 21% (p<0.001) Overall Survival: 27 vs. 25 mos (p=0.16) PFS (primary endpoint) Low: 8.7 vs 8 mos (p=0.03) High: 8.8 vs 8 mos (p=0.0099) ORR: Low: 55 vs 44% (p=0.03) High: 63 vs 44% (p=0.0001) Overall Survival: No sig. difference PFS (primary endpoint) X: 8.7 vs. 5.7 mos (p=0.0002) A/T: 9.2 vs. 8 mos (p<0.0001) ORR: X: 35 vs 24% (p=0.0092) A/T: 51 vs 38% (p=0.0054) Overall Survival: Not mature Miller K et al. New England J Med 2007; 357(26):2666 76; Miles D et al, J Clin Oncol 2008;26:50s, Abstract 1036; Robert N et al. J Clin Oncol 2009; 27:18s:, Abstract 1005.
RIBBON 2: Phase III Trial of Second Line Bevacizumab + Chemotherapy Patients with previously treated MBC (HER2 negative or HER2 status unknown) (N = 684) Chemotherapy Regimens* Taxane or Gemcitabine or Capecitabine or Vinorelbine Bevacizumab 15 mg/kg every 3 wks or 10 mg/kg every 2 wks + Chemotherapy (n = 459) Stratified by chemotherapy regimen, time between MBC diagnosis and first PD, and hormone receptor status; randomized 2:1 Placebo + Chemotherapy (n = 225) Treat until disease progression *Dose and schedule of chemotherapy regimens (selected by investigator): Taxane: paclitaxel 90 mg/m 2 /wk for 3 of 4 wks; paclitaxel 175 mg/m 2, nab paclitaxel 260 mg/m 2, or docetaxel 75 100 mg/m 2 every 3 wks. Gemcitabine 1250 mg/m 2 on Days 1 and 8 every 3 wks. Capecitabine 2000 mg/m 2 on Days 1 14 every 3 wks. Vinorelbine 30 mg/m 2 /wk every 3 wks. Dose of bevacizumab dependent on chemotherapy regimen used. Brufsky A, et al. SABCS 2009. Abstract 42. Brufsky A et al. SABCS 2009, Abstract 42.
Proportion of Progression Free Patients at Risk, n Chemo/placebo Chemo/bev RIBBON 2: Progression Free Survival 1.0 0.8 0.6 0.4 0.2 0 0 Primary Endpoint of PFS, ITT Population Median PFS: 7.2 vs. 5.1 mos HR: 0.78 (P =.0072) Duration of PFS (Mos) Chemo/placebo (n = 225) Chemo/bevacizumab (n = 459) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 225 165 129 93 77 44 33 19 12 8 5 4 3 1 1 0 0 0 459 381 334 254 190 130 87 47 27 18 9 5 2 1 1 0 0 0 Brufsky A, et al. SABCS 2009. Abstract 42. Brufsky A et al. SABCS 2009, Abstract 42.
Chemo/Bev Chemo p value PFS (1⁰ endpoint) 7.2m 5.1m 0.0072 ORR 40% 30% 0.02 OS (median) 18m 15m 0.37 Median F/u: 15 mo Drugs: Taxane 44% Gemcitabine 23% Capecitabine 21% Vinorelbine 11% PFS: Chemo/Bev Chemo Taxane 8.0m 5.8m Gem. 6.0m 5.5m Cape 6.9m 4.1m Vin 5.7m 7.0m Brufsky A et al. SABCS 2009, Abstract 42.
RIBBON 2: Phase III Trial of Second Line Bevacizumab + Chemotherapy Study met primary endpoint Improved PFS with bevacizumab + standard chemotherapy vs chemotherapy alone for second line treatment of HER2 negative MBC Observed improvement in PFS supported by secondary endpoint of ORR OS data immature Bevacizumab combination chemotherapy regimens well tolerated with no unexpected adverse events Feasible to consider bevacizumab in second line setting Brufsky A, et al. SABCS 2009. Abstract 42.
SOLTI 0701: Phase IIb Study of Combination Sorafenib + Capecitabine LABC/Stage IV < 1 prior chemo HER2 neg Sorafenib 400 mg PO BID continuously + Capecitabine 100 mg/m 2 PO BID for 14 of 21 days (n = 115) Stratified by visceral vs nonvisceral disease (N = 229) Placebo PO BID continuously + Capecitabine 100 mg/m 2 PO BID for 14 of 21 days (n = 114) Until disease progression or unacceptable toxicity Baselga J, et al. SABCS 2009. Abstract 45. Baselga J et al. Eur J Cancer;7 (supp):3
Sorafenib (Targets VEGFR, PDGFR, Flt 3, c Kit, MET) Sorafenib Sorafenib Wilhelm SM, et al. Cancer Res. 2004 Oct 1:64(19):7099 109.
Progression Free Survival: Intent to Treat Population PFS Probability 1.00 0.75 0.50 0.25 SOR + CAP N=115 PL + CAP N=114 Median PFS, mos 6.4 4.1 HR (95% CI) 0.576 (0.410 0.809) P = 0.0006* 42% reduction in the risk of disease progression SOR+CAP 0.00 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0 13.5 15.0 Months PL+CAP *One sided Baselga J et al. Eur J Cancer;7 (supp):3
Progression Free Survival: Sensitivity Analyses Analysis Median PFS (mos) SOR PL + +CAP CAP P Value* ITT 6.4 4.1 0.0006 First-line therapy 7.6 4.1 0.0022 Second-line therapy 5.7 4.1 0.0339 Per-protocol 6.0 4.0 0.0005 NPT as PFS event 5.8 4.0 0.0005 Favors SOR+CAP 0.576 0.498 0.652 0.541 0.599 0.614 Favors PL+CAP NPT not considered 6.4 4.1 0.0015 *One sided NPT=non protocol anti cancer therapy ; PL=placebo (protocol prohibited new anti cancer treatment or surgery) 0.25 0.5 0.75 1 1.25 1.5 HR (95% CI) Baselga J et al. Eur J Cancer;7 (supp):3
Adverse Event Rates* Overall incidence > 10% and Grade 3/4 2% in either treatment arm Sorafenib + Capecitabine (N=112) Placebo + Capecitabine (N=112) All (%) Grade 3 (%) Grade 4 (%) All (%) Grade 3 (%) Grade 4 (%) HFSR 89 45-63 13 - Diarrhea 53 5 0 30 5 0 Mucosal inflammation 32 1 0 19 3 1 Asthenia 24 0 0 27 2 0 Rash 22 3 0 8 0 0 Hypertension 17 1 0 12 2 0 Fatigue 14 2 0 13 1 0 Musculoskeletal pain 12 2 0 6 0 0 Dyspnea 12 5 0 12 3 1 Neutropenia 11 4 1 4 2 1 *Treatment emergent Baselga J et al. Eur J Cancer;7 (supp):3
SOLTI 0701: Phase IIb Study of Sorafenib + Capecitabine Sorafenib + capecitabine 42% reduction in risk of disease progression or death PFS benefit observed in subgroup analyses PFS benefit noted in both first line and second line Increased incidence of hand foot syndrome reported in sorafenib/capecitabine arm Phase III registration trial planned for sorafenib/ capecitabine in advanced breast cancer
NEW DEVELOPMENTS IN CHEMOTHERAPY HER2 Driven
BCIRG 006: Third Analysis (Last one, they promise) AC T 4 x AC 4 x Docetaxel 60/600 mg/m 2 100 mg/m 2 Her 2+ (Central FISH) N+ or high risk N N=3,222 AC TH TCH 4 x AC 4 x Docetaxel 60/600 mg/m 2 100 mg/m 2 1 Year Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab Slamon D., SABCS 2009.
BCIRG 006: Disease Free Survival Months from randomization Node negative subset ~ 300 per arm; ~ 100 events ACTH HR 0.47 (0.28 0.77) TCH 0.64 (0.41 1.01) No interaction benefit with risk HR 4+ LN 0.66 both H arms Slamon D., SABCS 2009.
BCIRG 006: Survival Months from randomization Slamon D., SABCS 2009.
BCIRG 006: Toxicity Median EF over time Months from randomization AC T TCH AC TH CHF 0.7% 0.4% 2.0% Cardiac death 0 0 0 OS (median) 18m 15m 0.37 Leukemia 0.6% (6) 0.1% (1) 0.1% (1)
BCIRG 006 Adding trastuzumab to chemo works TCH is a reasonable alternative, especially in patients with cardiac issues. Underpowered but inevitable comparisons of TCH vs AC TH suggest higher efficacy but more CHF Stipulating that this is an underpowered analysis : Suggestion that this benefit is largely confined to Topo II nonamplified (which are the majority) in topo II + you can either add H or give anthracycline, and both looked a little better than one.
n=3,505 R A N D O M I Z E N9831: Arm B Efficacy Analysis (Finally) Arm A: AC q 3w x 4 Arm B: AC q 3w x 4 Arm C: Cumulative cardiac events: AC q 3w x 4 Paclitaxel qw x 12 Paclitaxel qw x 12 Paclitaxel qw x 12 + H qw x 12 AC TH H AC T H RT and/or hormonal therapy as indicated N9831 H qw x 52 H qw x 40 AC T Perez EA et al, JCO 2008; Perez EA et al, SABCS 2009.
Alive and disease free (%) 100 90 80 70 60 50 40 1097 1087 Control (A) vs Sequential (B) Disease Free Survival Logrank p=0.0005 735 728 675 643 85.2% 79.7% 624 581 586 529 80.1% 71.9% 0 1 2 3 4 5 Years from randomization Perez EA et al, SABCS 2009. AC T H (164 events) AC T (222 events) 513 447 N9831 No. at risk
Alive and disease free (%) 100 90 80 70 60 Sequential (B) vs Concurrent (C) Disease Free Survival Logrank p=0.0190 89.1% 85.7% AC T+H H ( 138 events) AC T H (174 events) 84.2% 79.8% N9831 50 40 949 954 837 830 788 766 740 705 676 641 0 1 2 3 4 5 Years from randomization 456 418 No. at risk Perez EA et al, SABCS 2009.
Results: Disease Free Survival N9831 Joint Analysis (N9831/B31) ~3 yr median follow up 1 Pairwise comparison AC T vs AC T+H H *Stratified nodal status and receptor status Number of events P value 619 <0.00001 Adj HR (95%CI) 0.48 (0.41-0.57) N9831 Analysis (N9831) >5 yr median follow up 2 A B B C Pairwise comparison AC T vs AC T H (n=2,184) AC T H vs AC T+H H (n=1,903)* Number of events Log rank P value Adj HR* (95%CI) 386 0.0005 0.67 (0.55-0.82) 312 0.0190 0.75 (0.60-0.94) *Excluding pts on Arm B entered when Arm C was closed 1 Perez EA et al. J Clin Oncol 2007; 2 Perez EA et al. SABCS 2009 #701.
Results: Overall Survival N9831 Joint Analysis (N9831/B31) ~3 yr median follow up 1 Pairwise comparison AC T vs AC T+H H Number of events P value 258 0.0007 Unadj HR (95%CI) 0.65 (0.51-0.84) N9831 Analysis (N9831) >5 yr median follow up 2 Pairwise comparison Number of events Log rank P value Unadj HR* (95%CI) A B AC T vs AC T H (n=2,184) 220 0.281 0.86 (0.65-1.13) B C AC T H vs AC T+H H (n=1,903)* 168 0.135 0.79 (0.59-1.08) *Excluding pts on Arm B entered when Arm C was closed 1 Perez EA et al. J Clin Oncol 2007; 2 Perez EA et al. SABCS 2009#701.
Conclusions Adjuvant trastuzumab works It is probably better to give adjuvant trastuzumab concurrently with chemotherapy, although cardiac toxicity is higher.
Phase II Trial of Her TC in Patients with HER2+ Early BC Accrual: 263 (260 in cardiac safety population) Eligibility T1-2, N0-1 Her2+ (IHC 3+ or FISH+) LVEF 50% by MUGA or ECHO Docetaxel (T) Cyclophosphamide (C) Trastuzumab (H) T = 75mg/m 2 IV q 3 weeks x 4 C = 600mg/m 2 IV q 3 weeks x 4 H = 4mg/Kg Wk 1 2mg/Kg/week Wk 2-12 6mg/Kg q 3 weeks Wk 13-52 Cardiac events: Sixteen patients (6.1%) LVEF decline to 50% any time during treatment. Nine patients (3.4%) discontinued trastuzumab due to decrease in LVEF. No cases of CHF. 17.5% study discontinuation (patient ~5%, toxicity ~10%) Jones SE, SABCS 2009.
Other HER2 Directed Agents
Phase I/II Neratinib Combination Studies (Phase II part) With Paclitaxel >50% 2 nd + line, 15% 1 st line 30% prior H, 15% prior L With Vinorelbine >70% 2 nd + line, 0% 1 st line 100% prior H Diarrhea (any grade) > 90%. This is the issue for neratinib (also lapatinib) combinations. Chow, SABCS 2009, Abs 5081; Awada, SABCS 2009, Abs 5095.
Trastuzumab DM1 (T DM1), a HER2 Antibody Drug Conjugate Maytansine analogue DM1 (antitubule akin to vincas) conjugated to trastuzumab similar to gemtuzumab (Myelotarg) T MCC DM1 Y HER2 mediated internalization Beeram et al. J Clin Oncol 2008. Average number DM1 molecules/monoclonal antibody=3.5 T T MCC DM1 Lysine MCC DM1 Lysosomal degradation Active metabolite can t cross plasma membrane (no bystander effect)
50% ER+ T DM1 Phase II (n=100) Median time since stage IV diagnosis ~ 40 m (selected population) Heavily pretreated (prior A, T, X, H, L required): Krop I et al, SABCS 2009 #710.
T DM1 Efficacy Little cardiotoxicity, well tolerated Coming soon! Combination studies with other biologics in progress Krop I et al, SABCS 2009 #710.
Conclusions Genomic prognostic profiles are part of the armamentarium in all ER+ HER2 disease Caution can t ignore anatomy Lots of antiangiogenesis agents and studies largely in combination with chemotherapy. Bevacizumab works, but in whom? Sorafenib promising, but toxicity issues must be considered Studies in HER2+ disease T DM1 and others likely soon to be added to armamentarium!
Thank you