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Management of HER2 Positive Metastatic Breast Cancer PowerPoint Presentation

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Management of HER2 Positive Metastatic Breast Cancer
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Breast Cancer: Background Leading Cause of Cancer for Women Risk of developing over lifetime: 1 in 8 230,480 new cases estimated for 2011 Improved public awareness and screening programs have contributed to early detection and diagnosis Metastatic Breast Cancer (MBC) 20% with localized disease will develop distant metastases within 5 years of their initial diagnosis despite treatment 5-year survival rate of 23% 2 American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011. American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society; 2009. Gradishar W. Curr Oncol Rep. 2011;13:11-16.
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3 3 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet. 2011. Breast Cancer Mortality Breast cancer mortality has dropped by nearly one-third since 1990
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Factors Associated With Treatment of Metastatic Breast Cancer Incurable Treatment is palliative ER / PR / HER2 status Treatment resistance & adverse effects Chemotherapeutic agents may exhibit initial efficacy; however, the development of resistance to therapy and tolerability are concerns 4 Gradishar W. Curr Oncol Rep. 2011;13:11-16.
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HER2 POSITIVE BREAST CANCER Accounts for 15-20% of breast cancer cases Short DFS and OS compared to other subtypes when treated with conventional therapy HER2 targeted therapy dramatically changed outcome Multiple agents available: questions about optimal sequencing 5 Gradishar W. Curr Oncol Rep. 2011;13:11-16.
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6 Akt SOS RAS RAF MEK VEGF MAPK P P P P Receptor-specific ligands HER1, HER2, HER3, or HER4 HER2 HER1 (EGFR) HER2 HER4 HER3 Tyrosine kinase domains Plasma membrane PI3K Cell proliferation Cell survival Cell mobility and invasiveness Cytoplasm Nucleus Transcription Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness Ross JS, et al. The Oncologist. 2009;14:320-368.
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Slamon D, et al. Science 1987;235:177–82. Pauletti G, et al. J Clin Oncol 2000;18:3651–64. Shortened median survival* HER2 positive 3 years HER2 normal 6–7 years HER2 protein overexpression Targeting HER2: Scientific Rationale HER2 gene amplification *combined metastatic and adjuvant patients
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Ross JS, et al. 1988 OS of lymph node negative breast cancer by HER2 status
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HER2+ Breast Cancer Subtypes 9 Breakdown of the 21% HER2+ Bauer K., Cancer. 2010;10:228. 0.5% N=114,786 ~21% HER2+ ~79% HER2- 7.1% 10.8% 3.3%
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10 Onitilo A. Clin Med Res Opin. 2009;7(2):4-13. Survival for HER2+ Subtypes Clinical and pathologic features and survival of the four subtypes were compared In ER/PR+,HER2-, chemotherapy conferred significant overall survival advantages Subtype comparison revealed statistically significant differences in outcomes
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Optimal Testing Algorithm Immunohistochemistry (IHC) Breast Cancer Specimen (invasive component) Equivocal for HER2 protein expression IHC 2+ Equivocal HER2 gene amplification (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials) Positive for HER2 protein expression IHC 3+ (defined as uniform intense membrane staining of >30% of invasive tumor cells) Negative for HER2 protein expression IHC 0 or 1+ Negative for HER2 gene amplification Positive for HER2 gene amplification HER2 testing by validated IHC assay for HER2 protein expression Test with validated assay for HER2 gene amplification
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Breast Cancer Specimen HER2 testing by validated FISH assay for HER2 gene amplification Equivocal for HER2 gene amplification (FISH ratio 1.8-2.2 or HER2 gene copy 4.0-6.0) Count additional cells for FISH or retest, or test with HER2 IHC Equivocal HER2 gene amplification result (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials) Positive for HER2 gene amplification (FISH ratio >2.2 or HER2 gene copy >6.0) Negative for HER2 gene amplification (FISH ratio <1.8 or HER2 gene copy <4.0) HER2 gene no amplification FISH negative HER2 gene amplification FISH positive Optimal Testing Algorithm FISH
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FISH evaluation of HER2 status based on 2013 ASCO/CAP scoring criteria. (A and B) Evaluate 20 tumor cells; a HER2/CEP17 ratio≥2.0 is defined as HER2 gene amplification. (C) HER2/CEP17 ratio<2.0 but average HER2 copy number≥6.0 is defined as HER2-positive. (D) HER2/CEP17 ratio<2.0 and average HER2 copy number<4.0 signals/cell is defined as HER2-negative. (E and F) Previous HER2-negative cases defined based on the 2007 ASCO/CAP guideline were redefined as HER2-amplified. A HER2/CEP17 ratio<2.0 and average HER2 copy number≥4.0 and <6.0 signals/cell was defined as HER2-equivocal. Red, HER2; green, CEP17.
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HER2 Targeted Agents Monoclonal Antibodies Trastuzumab Pertuzumab “Ado-Trastuzumab” Tyrosine Kinase Inhibitors Lapatinib Neratinib Tucatinib
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The HER2-Targeted Therapeutic: Trastuzumab, a Humanized Anti-HER2 mAb Targets HER2 protein Selectively binds with high affinity Carter P, et al. Proc Natl Acad Sci U S A 1992;89:4285-4289. Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2010. mAb=monoclonal antibody M1.H.BC.Adv.Ow.17
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The HER2-Targeted Therapeutic: Trastuzumab MOA Humanized monoclonal antibody specific for HER2 Targets HER2 protein- overexpressing cells Proposed MOA based on preclinical studies Extracellular Intracellular Arnould L, et al. Br J Cancer 2006;94:259-267. Bianco AR. J Chemother 2004;16(suppl 4):52-54. Harari D, Yarden Y. Oncogene 2000;19;6102-6114. Lewis GD, et al. Cancer Immunol Immunother 1993;37:255-263. Sliwkowski MX, et al. Semin Oncol 1999;26(suppl 12):60-70. Yakes FM, et al. Cancer Res 2002;62:4132-4141. Yarden Y. Oncology 2001;61(suppl 2):1-13. Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2010. MOA=mechanism of action
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Lapatinib Drug Profile Belongs to the 4-anilinoquinazoline class of tyrosine kinase inhibitors Binds reversibly to the cytoplasmic ATP-binding site of the kinase, thereby preventing receptor phosphorylation and activation Works intracellularly N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- [5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Lapatinib is the first-in-class oral small-molecule inhibitor HER2 tyrosine kinase: Xia W, et al. Oncogene. 2002;21:6255-6263.
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18 Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263. Lapatinib: Targeting HER2 and EGFR Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 Blocks signaling through EGFR and HER2 homodimers and heterodimers May also prevent signaling between ErbB1/ErbB2 and other ErbB family members
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Ligand-activated HER2:HER3 dimer HER2 HER3 P P P P Pertuzumab Mechanism of Action: HER2 Dimerizes Preferentially With HER3 to Drive Downstream Signaling Baselga, Swain. Nat Rev Cancer 2009 9:463-475. Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127-137 Graus-Porta, et al. EMBO J 1997 1647-1655. Tzahar, et al. Mol Cell Biol 1996;16:5276-5287. Lee-Hoeflich, et al. Cancer Res 2008;68:5878-5887. Phosphorylation of the HER3 intracellular domain by HER2 initiates a signaling cascade M1.P.BC.Adv.Ow.6
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Pertuzumab Mechanism of Action: HER2:HER3 Dimers Initiate the Strongest Mitogenic Signaling Tzahar, et al. Mol Cell Biol 1996;16:5276-5287. Citri, et al. Exp Cell Res 2003;284:54-65. Huang, et al. Cancer Res 2010;70:1204-1214. Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER4 HER3:HER4 Signaling activity + + + + + + + + + + + + + + + + + HER2:HER3 M1.P.BC.Adv.Ow.7
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Akt Shc Pertuzumab Mechanism of Action: HER2:HER3 Dimerization Initiates Multiple Signaling Pathways, Including Increased Tumor Cell Proliferation Downstream PI3K/Akt signaling is mainly mediated by HER3 after transphosphorylation by HER2 HER2 HER3 GRb2 Sos RAS PI3K P P P P PDK1 P P P RAF MEK MAPK P P mTOR Cyclin 01 GSK36 NF  B BAD p27 Angiogenesis Proliferation Cell cycle control Apoptosis Survival Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127-137. Olayioye, et al. EMBO J 2000;19:3159-3167. Kim, et al. J Biol Chem 1994;269:24747-24755. Soltoff, et al. Mol Cell Biol 1994;14:3550-3558. Baselga, Swain. Nat Rev Cancer 2009;7:463-475 Rowinsky. Annu Rev Med 2004;55:433-457. M1.P.BC.Adv.Ow.8
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Pertuzumab Mechanism of Action: New Class of Targeted Anticancer Therapeutic Agents Called HER2 Dimerization Inhibitors 1. Agus, et al. Cancer Cell 2002;2:127-137. 2. Baselga. Cancer Cell 2002;2:93-95. 3. Citri, et al. Exp Cell Res 2003;284:54-65. 4. Franklin, et al. Cancer Cell 2004;5:317-328. 5. Hughes, et al. Mol Cancer Ther 2009;8:1885-1892. By blocking HER2 dimerization, pertuzumab inhibits key HER signaling pathways that mediate cancer cell proliferation and survival1-4 Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5 HER2 Dimerization domain Pertuzumab HER3 M1.P.BC.Adv.Ow.9
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T-DM1: Mechanism of Action Adapted from LoRusso PM, et al. Clin Cancer Res. 2011;17:6437-6447. Emtansine release Inhibition of microtubule polymerization Internalization HER2 T-DM1 Lysosome Nucleus P P P
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Neratinib overview Neratinib is an oral, irreversible tyrosine kinase inhibitor of ERBB1, 2, 4 (HER1, 2, 4 receptors) x
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ONT-380 (Tucatinib)
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Front Line Therapy
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The HER2-Targeted Therapeutic: Trastuzumab, a Humanized Anti-HER2 mAb Targets HER2 protein Selectively binds with high affinity Carter P, et al. Proc Natl Acad Sci U S A 1992;89:4285-4289. Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2010. mAb=monoclonal antibody M1.H.BC.Adv.Ow.17
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Trastuzumab as First-line Monotherapy for HER2+ MBC: Response by FISH Analysis No. of evaluable patients 82 29 CR 7 0 PR 21 2 ORR (%) 28 (34) 2 (7) 95% CI 24–45 1–23 Clinical benefit* 39 (48) 3 (10) FISH– n (%) FISH+ n (%) * CR + PR + MR + SD > 6 mo. Update of Vogel et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 86. IHC 2+/3+ combined
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Baselga et al. Cancer Res. 1998;58:2825. Herceptin/doxorubicin Herceptin/paclitaxel Control Herceptin Herceptin + chemotherapy Chemotherapy Herceptin® + Chemotherapy in Tumor Xenograft Studies
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AC=doxorubicin (60mg/m2) [or epirubicin (75mg/m2)] + cyclophosphamide (600mg/m2) q3w for 6 cycles; Taxol (175mg/m2 x 3 h) q3w for 6 cycles; Herceptin (4mg/kg) loading dose, 2mg/kg qw until progression; CT=chemotherapy; KPS=Karnofsky Performance Score; q3w=every three weeks; qw=weekly No prior adjuvant AC Prior adjuvant AC Taxol (n=96) Herceptin + Taxol (n=92) AC (n=138) Herceptin + AC (n=143) Stratify Randomize Randomize Slamon D, et al. N Engl J Med 2001;344:783. n=469 MBC HER2+ No prior CT for MBC Measurable disease KPS ³60% Herceptin Combination Pivotal Trial in First-line MBC: Schema
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Herceptin Combination Pivotal Trial: Efficacy Summary DR=duration of response; H=Herceptin; ORR=overall response rate; T=Taxol; TTP=time to progression; m=months; Herceptin Package Insert 2002. Slamon D, et al. N Engl J Med 2001;344:783. * * Study was not powered to show a survival difference in subgroups.
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Herceptin Combination Pivotal Trial: Overall Survival Update of Mass R, et al. Proc Am Soc Clin Oncol 2001;20;22a:abstract 85. RR=0.71 p=0.007 20.0 m 26.2 m RR=1.11 p=NS 19.8 m 24.0 m FISH– FISH+ Probability of survival 1.0 0.8 0.6 0.4 0.2 0 0 10 20 30 40 50 H+CT (n=176) CT (n=169) H+CT (n=50) CT (n=56) 1.0 0.8 0.6 0.4 0.2 0 0 10 20 30 40 50 Months Months CT=chemotherapy; NS=not significant; RR=response rate Survival advantage was demonstrated for first-line H + CT despite 66% of CT group receiving H in second or later lines of therapy
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Taxane + Lapatinib vs Trastuzumab as First-Line Therapy – Phase III NCIC CTG MA.31 Primary Endpoint: PFS Gelmon KA, et al. J Clin Oncol. 2015;33(14):1574-1583. *Paclitaxel 80 mg/m2 IV q1w, days 1, 8, 15 or docetaxel 75 mg/m2 IV q21d. †6 mg/kg IV q1w (load 4 mg/kg then 2 mg/kg) or 14 mg/kg q3w (load 8 mg/kg then 6 mg/kg). R Maintenance 24 Weeks
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Lapatinib + Taxane vs Trastuzumab + Taxane Progression-Free Survival Gelmon KA, et al. J Clin Oncol. 2015;33(14):1574-1583. Intent-to-treat population mOS not reached HR = 1.28 95% CI 0.95-1.71 P = 0.11 0 4 12 20 28 36 40 80 8 16 24 32 40 286 326 125 48 14 2 229 88 25 9 0 287 326 TTax/T No. at risk LTax/L 84 28 4 0 207 53 15 1 0 10 0 20 60 Time (m on t h s) Survival (%) TTax/T LTax/L Ttax/T = trastuzumab + taxane, trastuzumab maintenance Ltax/L = lapatinib + taxane, lapatinib maintenance
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MA.31 Trial Grade 3/4 Adverse Events Gelmon KA, et al. J Clin Oncol. 2015;33(14):1574-1583.
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Phase III CLEOPATRA Study Design First-Line Pertuzumab for MBC HER2+ MBC (N = 800) Docetaxel 75 mg/m2* q3wk + Trastuzumab 8 mg/kg, → 6 mg/kg q3wk + PLACEBO Docetaxel 75 mg/m2 q3wk +Trastuzumab 8 mg/kg, → 6 mg/kg q3wk + Pertuzumab 840 mg cycle 1, 420 mg q3wk *Docetaxel can be increased to 100 mg/m2 q3wk if tolerable. Primary endpoint: PFS 90% of enrolled patients trastuzumab naïve Baselga J, et al. N Engl J Med. 2012;366(2):109-119. Swain SM, et al. N Engl J Med. 2015;372(8):724-734. R
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CLEOPATRA: PFS Investigator Assessment Swain SM, et al. N Engl J Med. 2015;372(8):724-734. 100 90 80 70 60 50 40 30 20 10 0 PFS (%) T ime (months) HR 0.68 , 95% CI [0.58, 0.80], P < 0.001 Pertuzumab + T + D: median = 18.7 months Placebo + T + D: median = 12.4 months 6.3 Months 80 70 60 50 40 30 20 10 0 402 406 284 223 179 1 10 121 75 87 51 37 21 6 6 0 0 0 0 n at risk T, trastuzumab; D, docetaxel. Pertuzumab Placebo
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CLEOPATRA: OS Swain SM, et al. N Engl J Med. 2015;372(8):724-734. Pertuzumab + T rastuzumab + Docetaxel Median OS: 56.5 months Placebo + T rastuzumab + Docetaxel Median OS: 40.8 months HR = 0.68, 95% CI [0.56-0.84], P < 0.001 Median follow-up: 50 months (range, 0-70 months) 100 90 80 70 60 50 40 30 20 10 0 T ime (months) OS (%) 70 60 50 40 30 20 10 0 1 28 104 226 268 318 371 402 0 23 91 179 230 289 350 406 n at risk Δ = 15.7 months Pertuzumab Placebo
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CLEOPATRA: Safety Profile Swain SM, et al. Oncologist. 2014;19(7):693-701; Swain SM, et al. N Engl J Med. 2015;372(8):724-734. Serious AE
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Recommendations for First-Line Treatment of HER2+ MBC
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Phase III MARIANNE Study Design T-DM1 +/- Pertuzumab HER2+ Progressive or recurrent locally advanced or chemotherapy-naïve MBC (N = 1092) T-DM1 + PERTUZUMAB q3wk T-DM1 + PLACEBO q3wk Primary endpoint: PFS TRASTUZUMAB q3wk + DOCETAXEL q3wk OR PACLITAXEL qwk Ellis P, et al. J Clin Oncol. 2015;33(suppl). Abstract 507. R
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Second Line Therapy Trastuzumab beyond progression Novel agents (lapatinib, pertuzumab, Ado-trastuzumab) Dual HER2 blockade Investigational agents: neratinib, tucatinib
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R A N D O M I Z E German Breast Group 26/Breast International Group 03-05 Study: Trastuzumab Beyond Progression in HER2 Positive Advanced Breast Cancer Patients on treatment until progression or unacceptable toxicity, then followed for survival Trastuzumab + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk Progressive, HER2+ MBC or LABC Previously treated with trastuzumab* 1 prior chemotherapy regimen N=156 *Trastuzumab must have been administered for metastatic disease. von Minckwitz G et al. J Clin Oncol 2009.
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German Breast Group 26/Breast International Group 03-05: Results Trastuzumab beyond progression: disease-related death and death.
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Lapatinib Drug Profile Belongs to the 4-anilinoquinazoline class of tyrosine kinase inhibitors Binds reversibly to the cytoplasmic ATP-binding site of the kinase, thereby preventing receptor phosphorylation and activation Works intracellularly N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- [5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Lapatinib is the first-in-class oral small-molecule inhibitor HER2 tyrosine kinase: Xia W, et al. Oncogene. 2002;21:6255-6263.
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R A N D O M I Z E EGF100151 Study Study Design Patients on treatment until progression or unacceptable toxicity, then followed for survival Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Stratification: Disease sites Stage of disease N=528 *Trastuzumab must have been administered for metastatic disease. Geyer C, et al. NEJM. 2006;355:2733-2743.
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Therapy with Lapatinib Resulted in a Significant Improvement in Time to Progression (1 of 2) Independent Assessment
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50 Overall Survival: Capecitabine ± Lapatinib 0.800 P-value (log-rank, 2-sided) 29 (18%) 29 (18%) Deaths 0.93 (0.55, 1.59) Hazard ratio (95% CI) NR NR Median OS 161 160 No. of pts Time (weeks) 0 10 20 30 40 50 70 90 Cumulative Survival (%) 0 10 20 30 40 50 60 70 80 90 100 60 80 Geyer C, et al. N Engl J Med. 2006;355:2733-2743. Capecitabine Lapatinib + Capecitabine
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A Randomized Study of Lapatinib (Tykerb/Tyverb®) in Combination with Trastuzumab versus Lapatinib Monotherapy in Patients with Heavily-Pretreated HER2+ Metastatic Breast Cancer Progressing on Trastuzumab Therapy J. O’Shaughnessy1, K. Blackwell2, H. Burstein3, AM. Storniolo4, G. Sledge4, S. Vukelja5 J. Baselga6, M. Koehler7, S. Laabs7, A. Florance7, D. Roychowdhury7 1Baylor Sammons Cancer Center, 5Texas Oncology, PA, US Oncology, Dallas, TX; 2Duke University Medical Center, Durham, NC; 3Dana-Farber Cancer Institute, Boston, MA; 4I.U. Simon Cancer Center, Indianapolis, IN; 6Vall d'Hebron University Hospital, Barcelona, Spain; 7Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA. Presented at the American Society of Clinical Oncology Annual Meeting, 2008.
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A Randomized Study of Lapatinib (Tykerb/Tyverb®) in Combination with Trastuzumab versus Lapatinib Monotherapy in Patients with Heavily-Pretreated HER2+ Metastatic Breast Cancer Progressing on Trastuzumab Therapy Blackwell K, et al J Clin Oncol 2012
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Total Blockade of HER2 May Provide Greater Anti-tumor Activity and Overcome Resistance HER1 - HER1 HER1 - HER2 HER1 - HER3 HER2 - HER2 HER2 - HER4 HER2 - HER3 HER1 - HER4 PTEN PTEN SOS RAS RAF MEK MAPK Cell proliferation Cell survival Cell mobility and invasiveness PI3K Akt MUC4 p95 PI3K Akt SOS RAS RAF MEK MAPK Transcription Hudis C. N Eng J Med 2007;357(1):39-51. Nahta R, Esteva F. Breast Cancer Res 2006;8(6):215. Slide developed by LifeBrand for GSK
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Lapatinib in HER2+ Breast Cancer Lines Trastuzumab-Conditioned BT474 Cells Lapatinib inhibits growth of BC cell lines that acquire resistance to a therapeutically relevant dose of trastuzumab Lapatinib in combination with trastuzumab is synergistic in HER2+ BC cell lines Konecny et al. Cancer Res. 2006;66:1630-1639 0 10 20 30 40 50 60 70 80 90 100 Fraction unaffected (%) 500 250 125 62 39 15 7 3 13 0.05 Nmol lapatinib Nmol trastuzumab 1.5 trastuzumab lapatinib MDA-MB-361 Cells x
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Tykerb in Combination with Trastuzumab Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome RANDOMI ZAT I ON Tykerb 1000 mg/day PO Trastuzumab 4→ 2 mg/kg IV qw N=148 Tykerb 1500 mg/day PO N=148 Stratification Factors Visceral Disease Hormone Receptor Key Inclusion HER2+(FISH+/ IHC3+) MBC Progression on Anthracycline Taxane Trastuzumab Progression on most recent trastuzumab regimen Crossover if PD after 4wk therapy (N=73)
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Tykerb in Combination with Trastuzumab Treatment Efficacy *Confirmed CR+PR †CR+PR+SD ≥ 6 mo
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Blackwell K JCO 2012
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ado-Trastuzumab Emtansine (T-DM1) Background: Dual Mechanism of Action (MOA) Emtansine release Inhibition of microtubule polymerization Internalization HER2 Lysosome Nucleus P P P Trastuzumab-specific MOA maintained Antibody: Trastuzumab Emtansine Cytotoxic: DM1 Stable linker: MCC Antibody–drug conjugate: T-DM1 Highly potent DM1a is internalized within HER2(+) cancer cells © 2014 Genentech, Inc. All rights reserved. Junttila T, et al. Breast Cancer Res Treat 2011;128:347-356. aDM1 is 24- to 270-fold more potent than taxane in cytotoxic assays M3.K.BC.Adv.Ow.8
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Carter PJ, Senter PD. Cancer J 2008;14:154-169. Chari RV. Acc Chem Res 2008;41:98-107. Lewis Phillips GD, et al. Cancer Res 2008;68:9280-9290. ado-Trastuzumab Emtansine (T-DM1) Background: A Novel Antibody-Drug Conjugate (ADC) (cont.) Monoclonal antibody trastuzumab Target Expression: HER2 Highly potent cytotoxic agent (DM1, a tubulin destabilizer) Cytotoxic Drug: DM1 Systemically stable Thioether Linker T-DM1 © 2014 Genentech, Inc. All rights reserved. M3.K.BC.Adv.Ow.7
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ado-Trastuzumab Emtansine (T-DM1) Background: Combines 2 Approaches to Target HER2(+) Cancer Targeted Intracellular Delivery of DM1 ado-trastuzumab emtansine binds to the HER2 receptor and is internalized DM1 is released inside the cell DM1 kills tumor cells by inhibiting microtubule assembly Trastuzumab Biologic Properties Blocks downstream HER2 signaling to inhibit proliferation of tumor cells Flags HER2-positive tumor cells for destruction via antibody-dependent cell-mediated cytotoxicity Inhibits HER2 shedding Combined Mechanism of Action Lewis Phillips GD, et al. Cancer Res 2008;68:9280-9290. Junttila T, et al. Breast Cancer Res Treat 2011;128:347-356. © 2014 Genentech, Inc. All rights reserved. M3.K.BC.Adv.Ow.9
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TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Study Design 1:1 HER2-Positive MBC Progressed on HER2-directed therapy or within 60 days after receiving trastuzumab ≥1 prior chemotherapy agent for MBC (N=112) T-DM1 3.6 mg/kg q3w up to 1 year A single-arm phase II US study aPatients who were still achieving clinical benefit after 1 year were eligible to transfer to an extension study Option of continued treatmenta Primary endpoint: ORR by independent review, safety and tolerability Burris HA III, et al. J Clin Oncol 2011;29:398-405. Key secondary endpoints: ORR by investigator assessment, DOR, PFS by independent and investigator assessment, and PK 66 M5.K.BC.Early.Ow.13 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Baseline Demographics and Disease Characteristics Burris HA III, et al. J Clin Oncol 2011;29:398-405. ER=estrogen receptor; PR=progesterone receptor 67 M5.K.BC.Early.Ow.14 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Efficacy Overview Burris HA III, et al. J Clin Oncol 2011;29:398-405. 68 aDifferences between the IRF- and investigator-determined ORR are attributed to the independent selection of different lesions by the reviewers and alternative interpretations of nontarget lesions; bAll partial responses; c4 (3.6%) complete responses and 38 (33.9%) partial responses IRF=independent review facility; NE=not estimable; NR=not reached M5.K.BC.Early.Ow.15 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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TDM4374g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in Previous Trastuzumab- and Lapatinib-Treated MBC: Study Design A single-arm phase II study Krop IE, et al. J Clin Oncol 2012;30:3234-3241. 69 Data cutoff for analysis was June 21, 2010. Median follow-up was 17.4 months CBR=clinical benefit rate; H=trastuzumab; L=lapatinib; X=capecitabine 1:1 T-DM1 3.6 mg/kg q3w HER2-Positive MBC Prior exposure to an anthracycline, a taxane, X, L, and H ≥2 HER2-directed therapy regimens for LABC or MBC Progression on most recent HER2-directed therapy regimen (N=110) Primary endpoint: ORR by independent review, safety and tolerability Key secondary endpoints: CBR (CR + PR + SD ≥6 months), DOR, PFS, and PK M5.K.BC.Early.Ow.19 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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TDM4374g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in Previous Trastuzumab- and Lapatinib-Treated MBC: Baseline Characteristics aInformation on ER/PR status was unknown for 4 patients; bExcluding hormonal therapies; c1 patient received prior ixabepilone instead of a taxane ER=estrogen receptor; PR=progesterone receptor Krop IE, et al. J Clin Oncol 2012;30:3234-3241. 70 M5.K.BC.Early.Ow.20 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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TDM4374g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in Previous Trastuzumab- and Lapatinib-Treated MBC: Efficacy Overview 71 1. Krop IE, et al. J Clin Oncol 2012;30:3234-3241. 2. Krop IE, et al. Presented at: ESMO. 2010 (abstr 2770). aObjective response rate = CR or PR determined by 2 consecutive tumor assessments ≥4 weeks apart; bAll partial responses; c4.5% complete responses CT=chemotherapy; H=trastuzumab; IRF=independent review facility; L=lapatinib; NE=not estimable M5.K.BC.Early.Ow.21 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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Phase III Trial: T-DM1 vs Capecitabine + Lapatinib EMILIA Study Design Verma S, et al. N Engl J Med. 2012;367(19):1783-1791. Co-Primary Endpoints: OS and PFS 61% of patients in each group had 0-1 prior chemo regimens for locally advanced or metastatic disease. 39% had > 1 prior regimen. R
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EMILIA* (TDM4370g) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in HER2-Positive MBC: Progression-Free Survival (PFS) by Independent Review 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Cap + Lap T-DM1 Patients at risk by independent review: 0.0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Proportion Progression Free Time, Months Verma S, et al. N Engl J Med 2012;367:1783-1791 [including supplementary appendix]. Unstratified HR=0.66 (95% CI, 0.56-0.78; P<0.0001) Cap=capecitabine; Lap=lapatinib Median PFS by investigator review: 9.4 for T-DM1 vs 5.8 months for Cap + Lap; HR=0.66; P<0.001 73 Stratified HR=0.65 (95% CI, 0.55-0.77) P<0.001 M5.K.BC.Early.Ow.46 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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EMILIA: Overall Survival Verma S, et al. N Engl J Med. 2012;367(19):1783-1791. Overall Survival (%) 10 0 8 0 6 0 4 0 2 0 0 0 6 1 2 1 8 2 4 3 0 4 1 0 1 6 2 2 2 8 2 8 1 4 2 0 2 6 M on t h s N o . a t Ri sk Lapa t i n i b – c ape c i t ab i n e T - D M 1 49 6 49 5 47 1 48 5 45 3 47 4 43 5 45 7 40 3 43 9 36 8 41 8 29 7 34 9 24 0 29 3 20 4 24 2 15 9 19 7 13 3 16 4 11 0 13 6 8 6 11 1 4 5 6 2 6 3 8 6 2 7 3 8 1 7 2 8 7 1 3 3 2 3 4 3 6 4 5 85 . 2 % ( 95% CI, 82.0-88.5) 64 . 7 % ( 95 % C I, 59 . 3-70.2) Lapa t i n i b– Capecitabine T - D M 1 78 . 4 % ( 95 % C I, 74 . 6-82.3) 51 . 8 % ( 95 % C I, 45 . 9-57.7)
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EMILIA: Safety Profile Verma S, et al. N Engl J Med. 2012;367(19):1783-1791. Serious AE
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T-DM1 vs Physician’s Choice – Beyond Second-Line HER2 Therapy (TH3RESA) Krop IE, et al. Lancet Oncol. 2014;15(7):689-699. Metastatic or unresectable locally advanced HER2+ BC Prior trastuzumab, taxane, and lapatinib (N = 602) T-DM1 3.6 mg/kg IV every 21 days n = 404 Physician’s choice: chemo, hormone therapy, biologic, HER2-targeted n = 198 Primary Endpoints: PFS, OS R 2 1
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TH3RESA* (BO25734) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Treatment of Physician’s Choice in HER2-Positive MBC: Progression-Free Survival (PFS) by Investigator Assessment 198 404 120 334 62 241 28 114 13 66 6 27 1 12 0 0 TPC T-DM1 Patients at risk: Time, Months 14 12 10 8 6 4 2 0.0 0.2 0.4 0.6 0.8 1.0 0 Proportion Progression Free Krop IE, et al. Lancet Oncol 2014;15:689-699. 77 Stratified HR=0.528 (95% CI, 0.422-0.661) P<0.0001 M5.K.BC.Early.Ow.96 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved. Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001) TPC=treatment of physician’s choice
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TH3RESA* (BO25734) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Treatment of Physician’s Choice in HER2-Positive MBC: Final Overall Survival (OS) Analysis Time, Months Proportion Surviving 78 TPC T-DM1 Patients at risk: M5.K.BC.Early.Ow.101 40 34 28 22 16 12 2 0.0 0.2 0.4 0.6 0.8 1.0 0 4 6 8 10 14 18 20 24 26 30 32 36 38 0 6 39 62 80 107 168 198 150 131 122 115 93 68 66 59 51 28 16 1 0 0 25 132 179 226 280 388 404 368 347 321 298 251 207 192 167 164 84 54 12 2 Wildiers H, et al. Presented at: SABCS. 2015 (abstr S5-05). *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved. TPC=treatment of physician’s choice Stratified HR=0.68 (95% CI, 0.54-0.85) P=0.0007 (Prespecified crossing boundary: HR<0.748; P<0.012)
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MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC: Study Design Ellis P, et al. Presented at: ASCO. 2015 (abstr 507). Trastuzumab + docetaxel (8 mg/kg LD then 6 mg/kg + 100 or 75 mg/m2 q3w) OR Trastuzumab + paclitaxel (4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw) T-DM1 + placebob (3.6 mg/kg + 840 mg LD then 420 mg q3w) R HER2-Positive (Central) LABCa or MBC No prior chemotherapy for LABC/MBC >6 months from prior (neo)adjuvant vinca alkaloid or taxane chemotherapy (N=1095) Primary endpoint: PFS by IRF, non-inferiority and superiority assessed Stratification factors: World region, prior neo-/adjuvant therapy (if yes: prior trastuzumab/lapatinib), visceral disease Key secondary endpoints: OS, PFS by investigator, ORR, safety, patient-reported outcomes T-DM1 + pertuzumab (3.6 mg/kg + 840 mg LD then 420 mg q3w) aLocally progressive or recurrent and not amenable to resection with curative intent; bPertuzumab placebo IRF=independent review facility; LD=loading dose 79 M5.K.BC.Early.Ow.111 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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Progression-Free Survival MARIANNE Trial Ellis P, et al. J Clin Oncol. 2015;33(suppl 15). Abstract 507. T i m e ( m o .) 0 6 18 30 42 54 40 80 12 24 36 48 365 265 107 50 5 163 75 21 363 261 135 75 5 177 109 25 367 HT T-DM1 + P T-DM1 257 133 67 3 176 104 28 1 10 0 20 0 60 Progression-Free Survival (%) HT T-DM1 + P T-DM1 HR, hazard ratio; HT, trastuzumab + taxane; P, pertuzumab; PFS, progression-free survival; T-DM1, trastuzumab emtansine. Median PFS (mo) Events (no.) Stratified HR (97.5% CI) vs HT Stratified HR (97.5% CI) vs T-DM1 13.7 231 - 15.2 217 14.1 HT T-DM1 + P T-DM1 236 0.87 (0.69-1.08) P = 0.14 0.91 (0.73-1.13) P = 0.31 0.91 (0.73-1.13) -
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MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC: Overall Survival (OS) (First Interim Analysis) 100 80 60 40 20 0 Survival, % 0 6 12 18 24 30 36 42 48 54 Time, Months 365 367 363 335 345 341 303 321 309 273 291 282 250 263 257 218 224 231 98 104 106 25 37 28 1 3 1 Ellis P, et al. Presented at: ASCO. 2015 (abstr 507). 82 HT=trastuzumab + taxane; NR=not reached; Pert=pertuzumab HT T-DM1 T-DM1 + Pert Patients at risk: M5.K.BC.Early.Ow.118 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC: Maintenance of HRQOL The FACT-Breast Trial Outcome Indexa evaluates Physical well-being Functional well-being and Breast cancer subscale 83 Ellis P, et al. Presented at: ASCO. 2015 (abstr 507). aHRQOL measured by the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire; bEvent was defined as ≥5-point decrease from the baseline HRQOL score (Eton, J Clin Epidemiol, 2004) HRQOL=health-related quality of life; HT=trastuzumab + taxane M5.K.BC.Early.Ow.120 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved.
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MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC: Overview of AEs Ellis P, et al. Presented at: ASCO. 2015 (abstr 507). 84 M5.K.BC.Early.Ow.121 *Roche Sponsored Study © 2016 Genentech, Inc. All rights reserved. HT=trastuzumab + taxane; LVEF=left ventricular ejection fraction
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Neratinib overview Neratinib is an oral, irreversible tyrosine kinase inhibitor of ERBB1, 2, 4 (HER1, 2, 4 receptors) x
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Neratinib Oral tyrosine kinase inhibitor of Her 1,2, 4 In vivo data: ↓ HER2 receptor phosphorylation Inhibits cell proliferation Xenografts Rapid and sustained tumor growth regression Phase 2 trial in trastuzumab pretreated (n=66) and naïve (n=70) patients ORR 24% and 56%, respectively 16 weeks PFS: 59% and 78%, respectively
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ExteNET: Phase III Study Design Primary endpoint: iDFS in ITT population at 2 yrs Results of primary analysis: 2-yr iDFS improved with neratinib vs placebo (93.9% vs 91.6%, HR: 0.67; P = .009) Hormone receptor+ (n = 1631): HR: 0.51; P = .001 HER2+ 60% (n = 1463): HR: 0.51; P = .002 Slide credit: clinicaloptions.com Chan A, et al. SABCS 2015. Abstract S5-02. Pts with HER2+ local BC; adj. trastuzumab completed ≤ 1 yr before study entry plus chemo; lymph node+ disease or no pCR; known ER and PgR status (N = 2840) iDFS: 2- and 5-yr F/U OS: 5-yr F/U Neratinib 240 mg/day Placebo 1 yr
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100 90 80 70 60 50 0 Neratinib (n = 1420) Placebo (n = 1420) 48 ExteNET Current Analysis: 3-Yr iDFS Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. Slide credit: clinicaloptions.com 2-sided P = .023 HR: 0.74 (95% CI: 0.56-0.96) 97.8% 95.6% 94.1% 91.6% 94.1% 89.9% 90.5% 88.6% 0 6 12 18 24 30 36 42 Disease-Free Survival (%) Mos After Randomization
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Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. ExteNET: 3-Yr iDFS by Hormone Receptor Status Slide credit: clinicaloptions.com 100 90 80 70 60 50 0 100 90 80 70 60 50 0 0 6 12 18 24 30 36 42 48 Mos After Randomization 0 6 12 18 24 30 36 42 48 Mos After Randomization Neratinib (n = 816) Placebo (n = 815) 2-sided P = .003 HR: 0.57 (95% CI: 0.39-0.82) Disease-Free Survival (%) Disease-Free Survival (%) 98.0% 96.1% 95.4% 91.5% 93.6% 89.3% 92.3% 87.9% Neratinib (n = 604) Placebo (n = 605) 2-sided P = .938 HR: 0.98 (95% CI: 0.67-1.45) 97.5% 94.9% 92.5% 91.8% 90.6% 89.9% 89.5% 88.1% Hormone Receptor Positive Hormone Receptor Negative
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