2015 GBCC & 4 th IBCS 1/37 Recent Update in Management of Breast Cancer: Medical Oncology Jin Hee Ahn, M.D., PhD. 23-April-2015 Department of Oncology, Asan Medical Center, UUCM, Seoul, Korea
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4/37 ER-positive breast cancer Endocrine therapy. and its potential new friends?
5/37 Combining targeted and antiestrogen therapies in HR positive breast cancer mtor Inhibitors Everolimus Sirolimus Temsirolimus CDK 4/6 Inhibitor Palbociclib LEE011 LY2835219 PI3K inhibitor BKM 120 GDC-0941 BYL 719 P RAS Cell Cycle EGFR HER2 RAF MEK P PI3K MAPK AKT TKI mtor PTEN E ER E ER E E E ER Aromatase Inhibitor Nonsteroidal AIs Anastrozole Letrozole Steroidal AIs Exemestane ER Downregulator Fulvestrant Selective Estrogen Rece ptor Modulators Tamoxifen Toremifene ER target gene transcription HDAC Inhibitor Entinostat Transcription Silencing
6/37 BOLERO-2: Everolimus + Exemestaine increase the PFS & OS of ER+ HER2- MBC Baselga J et al. NEJM 2012, 366: 520-529, Adv Ther 2013, 30: 870-84
PALOMA-1 Trial 7/37 Phase II Randomized study: ER +, HER2 MBC (1 st line) Palbociclib Primary endpoint: PFS
8/37 PALOMA1 trial: palbociclib + letrozole vs. letrozole median F/U: 29.6 mo Progression-Free Survival Overall Survival Palbociclib + Letrozole Letrozole Median PFS: 10.2 vs. 20.2 months (HR 0.488, 95% CI 0.319-0.748,P=0.0004) Finn RS et al. Lancet Oncol 2015; 16: 25
Most common Treatment-Related AEs 10% 9/37 Palbociclib+ Letrozole (N=83) Letrozole (N=77) Gr ½ (%) Gr 3 (%) Gr 4 (%) Gr ½ (%) Gr 3 (%) Gr 4 (%) Neutropenia 19 48 6 1 1 0 Leukopenia 23 18 0 0 0 0 Anemia 23 4 1 0 0 0 Fatigue 22 2 0 14 0 0 Alopecia 22 0 0 3 0 0 Hot flush 18 0 0 10 0 0 Arthralgia 17 0 0 9 1 0 Thrombocytopenia 14 2 0 0 0 0 Nausea 14 1 0 1 0 0 Decreased appetite 8 1 0 0 0 0 Stomatitis 10 0 0 0 0 0 Neutropenia was self-limited and not associated with infectious complications
10/37 Timeline of approval of agents for HR-positive advanced breast cancer Palbociclib (CDK 4/6 inhibitor) (2015) 2015
The PI3K/AKT/mTOR Pathway in Breast Cancer: Common Molecular Alterations 11/37 ~40% of HR + breast cancer have PIK3CA mutations Endocrine Rev. 2008; 29: 217-33. Baselga J. Oncologist 2011; 16: Suppl 1: 12
12/37 HER2-positive breast cancer New standard treatment for HER+ MBC
13/37 Singh JC et al. BJC 2014, 111: 1888 Molecular approaches to HER2 targeted therapy 1998 2012 2013 2005
Baselga J et al. NEJM 2012; 366: 109 14/37 CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting Study dosing q 3 week -Pertuzumab/placebo: -Trastuzumab: -Docetaxel: 840 mg loading 420 mg maintenance 8 mg/kg loading 6 mg/kg maintenance 75 mg/m 2 100 mg/m 2 escalation if tolerated
15/37 Baselga J et al. NEJM 2012; 366: 109 CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting PFS OS Median follow-up period: 19.3 months
16/37 Swain et al, ESMO 2014, NEJM 2015; 372: 724-734 CLEOPATRA: Final OS Analysis (median f/u 50 months) Median OS 56.5 vs. 40.8 months Difference: 15.7 months
LoRusso PM et al. Clin Cancer Res 2011 T-DM1 selectively delivers DM1 to HER2-positive tumor cells 17/37 Antibody-drug conjugate: T-DM1 Highly potent DM1 is internalized within HER2+ cancer cells
18/37 EMILIA study: Phase III trial of T-DM1 vs. Lapatinib+capecitabine after trastuzumab in HER2+ MBC Primary end points: PFS by independent review, OS, and safety Secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Sunil Verma et al. NEJM 2012; 367: 1783
19/37 EMILIA study: Progression-Free Survival 3.2 months Sunil Verma et al. NEJM 2012; 367: 1783
20/37 EMILIA study: Overall survival OS = 5.8 months Sunil Verma et al. NEJM 2012; 367: 1783
21/37 EMILIA study: Adverse Events in the Safety Population Cap + Lap (n=488) T-DM1 (n=490) All-grade AE, n (%) 477 (97.7) 470 (95.9) Grade 3 AE, n (%) 278 (57.0) 200 (40.8) AEs leading to treatment discontinuation (for any study drug), n (%) 52 (10.7) 29 (5.9) AEs leading to death on treatment, n (%) 5 (1.0) 1 (0.2) LVEF <50% and 15-point decrease from baseline, % 7 (1.6) 8 (1.7)
22/37 TH3RESA Study Schema Co-primary end points: PFS by investigator and OS Secondary end points: ORR by investigator and safety Krop IE et al, Lancet Oncol 2014, 15: 689-699
23/37 TH3RESA Study: PFS Krop IE et al, Lancet Oncol 2014, 15: 689-699
24/37 TH3RESA Study: First Interim Analysis of OS Krop IE et al, Lancet Oncol 2014, 15: 689-699
25/37 Current ASCO guidelines ER-/ER+ HER2 MBC ER+ (e.g. asymptomatic, low burden disease, patients at increased risk of toxicity from chemotherapy) Taxane/trastuzumab/pertuzumab Letrozole +/- Lapatinib AI or tamoxifen +/- Trastuzumab Ado Trastuzumab Emtansine (T-DM1) ER guidelines Lapatinib/Capecitabine Trastuzumab/Capecitabine Trastuzumab/Lapatinib Trastuzumab/Chemotherapy T-DM1 if not received earlier Pertuzumab if not received earlier * No OS advantage with hormone therapy plus anti-here2 therapy Giordano et al. JCO 2014 (ASCO Guidelines)
Can resistance to anti-her2 agents be overcome or modulated? 26/37
27/37 Triple Negative Breast Cancer (TNBC)
Molecular Heterogeneities of TNBC 28/37 SUBGROUPS Basal-like 1 Basal-like 2 Immunomodulatory Mesenchymal-like Mesenchymal stem-like Luminal AR Lehmann BD et al. J Clin Invest 2011, 121: 2750
Schematic illustration of overlap among TNBC, basal-like, and BRCA1-related tumors 29/37 (80%) Mayer et al. CCR 2014, 20: 782 BCRT 2011; 125: 627
How to Target Advanced TNBC? 30/37 High growth rate Increased sensitivity to chemotherapy? Impaired repair of DNA (Homologous Recombination Deficiency) * BRCA dysfunction Methylation Somatic mutation Other epigenetic mechanisms Blood vessel growth Increased sensitivity to platinum chemotherapy? PARP inhibitors? Role of angiogenesis Inhibitors (Bevacizumab)? * DFCI 2014
31/37 Platinum in unselected TNBC Regimen N Overall RR PFS (mo) Dz-free-interval (median) Gemcitabine/ 258 30% 4.1 15 months carboplatin 1 1 st line 2 nd /3 rd line 148 110 4.6 2.9 15.9 months 13.8 months Carboplatin or cisplatin 2 1 st line / 2 nd line 86 30% 32% / 20% 3.2 NA ORR in BRCA ½ mutant 55% vs. 26% in BRCA ½ wild type Highlights need for biomarkers of platinum response 1. ASCO 2011 (abstr) 2. ASCO 2011 (abstr)
32/37 TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC Patients with ER-, PgR-/ unknown, and HER2- or BRCA1/2+ metastatic or recurrent LA BC (N = 376) Carboplatin AUC6 q3w x 6 cycles (n = 188) Docetaxel 100 mg/m 2 q3w x 6 cycles ( n = 188) For both arms, crossover upon progression allowed Primary endpoint: ORR in ITT population Secondary endpoints: PFS, OS, ORR (crossover), toxicity Subgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers Tutt A, et al. SABCS 2014. Abstract S3-01.
Response at Cycle 3 or 6 (%) 33/37 TNT trial: Overall Response Rate 90 80 70 60 50 40 30 20 10 0 Survival, Mos Carboplatin Docetaxel 31.4% P =.44 35.6% All Pts (n = 376) Carboplatin Docetaxel Crossover Median PFS 3.1 4.5 BRCA 1/2 mutated 6.8 4.8 P =.03 BRCA 1/2 not mutated 3.1 4.6 68.0% Median OS 12.4 12.3 33.3% BRCA1/2 Mutation (n = 43) 28.1% P =.16 36.6% No BRCA1/2 Mutation (n = 273) Tutt A, et al. SABCS 2014. Abstract S3-01.
A new modality for breast cancer? Immune checkpoint agents and immunomodulators 34/37 T-cell Targets for Immunotherapy Mellman I et al. Nature 2011; 480 Pembrolizumab (Keytruda) [Anti PD-1 therapy] High affinity for the PD-1 receptor Recently approved in the US for the pts with unresectable or metastatic melanoma
Change From Baseline in Sum of Lo ngest Diameter of Target Lesion (%) 35/37 Phase Ib KEYNOTE-012: Pembrolizumab Holds Promise in TNBC, Early Studies Suggest Pts with recurrent or metastatic ER/ PgR-/HER2-, PD-L1+ BC (N = 32) Pembrolizumab 10 mg/kg q2w 100 80 60 40 20 0-20 -40-60 -80-100 Individual Evaluable Pts Overall Response rate: 18.5% (5/27) Stable disease: 25.9% (7/27) Progressive disease: 44.4% (12/27) Confirmed CR (nodal disease) Confirmed PR SD PD 3 responding pts on treatment for > 11 mos Nanda R, et al. SABCS 2014. Abstract S1-09.
36/37 TNBC: Current and Future Potential Therapeutic Targets
37/37 Recent update of systemic therapy: SUMMARY ER + MBC mtor inhibitor or CDK4/6 inhibitor with endocrine therapy to overcome endocrine resistance HER2 + MBC Pertuzumab and T-DM1 lead to improved outcomes with favorable toxicity. TNBC Recent renewed interest in investigating the role of platinum in TNBC. BRCA 1/2 mutation status: important potential biomarker for platinum therapy.
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CDK 4 and 6 inhibitor Oral, highly selective inhibitor of CDK4/6 kinase Prevent cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase
HER2 dimerization is essential for HER2 activity: Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity Pertuzumab trastuzumab More complete blockade of HER2 signal transduction
Loi et al. JCO 2013 TIL (tumor infiltrating lymphocyte) Higher levels in TNBC Lymphocyte-predominant BC Higher level of TIL = better survival in TNBC
Pembrolizumab in Advanced TNBC : Toxicity Adverse Events in 5%, % N = 32 Any Grade Grade 3-5 Arthralgia 18.8 0 Fatigue 18.8 0 Myalgia 15.6 0 Nausea 15.6 0 ALT increased 6.3 0 AST increased 6.3 0 Diarrhea 6.3 0 Erythema 6.3 0 Headache 6.3 3.1 (1 patient) Nanda R, et al. SABCS 2014. Abstract S1-09.
Cross-talk between signal transduction and endocrine pathways Endocrine Rev. 2008; 29: 217-33.
HER2 targeted therapy adds modestly to endocrine therapy PFS Anastrozole + Trastuzumab > Anastrozole Kaufman et al, JCO 2008 PFS Letrozole + Lapatinib > Letrozole Johnston et al, JCO 2009 Addition of HER2-directed therapy improves PFS but not OS
Choice of Chemotherapy in TNBC HR deficiency characterizes breast cancers in BRCA 1/2 mutation carriers Due to loss of heterozygosity at BRCA1 or BRCA2 HR deficiency implicated in some sporadic TNBC Methylation Somatic mutation Other epigenetic mechanisms
Ellis MJ et al. Nature 2012; 486: 353 Breast Cancer Genome Sequencing Results The genome wheels show point mutations, copy number changes, and chromosomal Translocations in aromatase inhibitor (AI) sensitive and AI-resistant breast cancers.
PI3K inhibitors in clinical development
SABCS 2014
25/37 Phase III trial: MARIANNE 1 st line HER2+ MBC