William J. Gradishar MD

Transcription

1 Northwestern University Feinberg School of Medicine Management of HER2+ MBC SOBO 2012 William J. Gradishar MD Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center for Women s Cancer Care Robert H. Lurie Comprehensive Cancer Center

2 Not all HER2+ disease is HER-E

3 Molecular Subtype and Therapeutic Questions Luminal B Luminal A Claudin-low HER2-enriched Basal-like Hormone receptor + Endocrine-dominant Triple negative (ER, PR, HER2) ER + subtypes Chemo-based HER2+ on on clinical assays (caner negative be ER + or -) subtypes HER2-targeting

4 HER2-Positive Breast Cancer NCIC MA.5 (N=88) NCIC MA.12 (N=66) Combined microarray dataset (N=81) Prat & Perou, Mol Oncol. 2011

5 Advancing HER2-Targeting Trastuzumab (H) * HER2 ECD monoclonal antibody PFS and OS in stage IV DFS (48%) and OS (39%) in adjuvant setting H after progression works Lapatinib (L) * Reversible HER1/2 inhibitor Approved in Stage IV Effective in H resistance Pertuzumab (P) * HER2 dimerization antibody Effective in H resistance Approved 1 st line with H (and chemo) Neratinib Irreversible HER1/2 inhibitor Activity in H resistant TDM1 HER2 antibody drug conjugate Less toxic than chemo + anti HER2 Menendez et al, JCO 07 * = FDA Approved in breast cancer

6 Chemotherapy Plus Trastuzumab in Metastatic Disease Slamon et al n = 469 Treatment arms AC or T* vs AC or T H Time to Disease Progression (mos) P value Marty et al n = 186 Docetaxel vs Docetaxel H P value < Response Rate 32% 50% < % 61% Median Overall Survival (mos) *T = paclitaxel; H = trastuzumab Hudis CA. N Engl J Med. 2007;357:36 51; Slamon DJ, et al. N Engl J Med. 2001;344: ; Marty M, et al. J Clin Oncol. 2005;23:

7 Why Not Continue Trastuzumab? GBG 26/BIG 3-05 (Closed Early With Poor Accrual) Women with HER2-positive advanced BC or MBC that progressed on Trastuzumab (N = 156) Capecitabine 2500 mg/m 2 /d on Days 1-14 q3w Capecitabine 2500 mg/m 2 /d on Days 1-14 q3w + Trastuzumab 6 mg/kg q3w von Minckwitz G, et al. 2006

8 Trastuzumab Remains Effective After Disease Progression Capecitabine Capecitabine + Trastuzumab von Minckwitz G, et al. 2009

9 Time To Progression at median Follow up of 15.6 months X : 5.6 ( ) mos XH : 8.2 ( ) mos P< HR=0.69 (two sided p=0.034; one sided p=0.017) Progression to CNS: X: 8.3% XH: 13.8% PFS X: 5.6 mos XH: 8.2 mos P=0.026 two sided von Minckwitz G, et al. J Clin Oncol 27: , 2009

10 TKI After Trastuzumab? HER2+ LABC or MBC with prior exposure to an Anthracycline, a Taxane and Trastuzumab* N = 324 Stratification: Disease sites Stage of disease R A N D O M I Z E Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk (n = 163) Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk (n = 161) Patients on treatment until progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease. Geyer CE, et al. 2006

11 Geyer CE, et al Lapatinib Increases Time to Progression After Trastuzumab

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15 HER2:HER3 dimers may provide an escape mechanism from trastuzumab Homodimers Heterodimers HER2:HER2 HER1:HER1 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER Signaling activity Tzahar, et al. Mol Cell Biol Sergina et al. Nature 2007, 445:

16 Pertuzumab and Trastuzumab Provide a More Comprehensive HER2 Blockade Trastuzumab HER2 Pertuzumab HER3 Subdomain IV of HER2 Dimerization domain of HER2 (subdomain II) Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 1 PertuzumabA blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4 1 Trastuzumab binds to subdomain IV and disrupts ligand-independent HER2 signaling 2 While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab significantly augmented antitumor activity in HER2-overexpressing xenograft models 1

17 CLEOPATRA: a phase III trial of trastuzumab plus pertuzumab in the first-line setting Docetaxel + Trastuzumab + PLACEBO HER2-positive MBC (n=800 a ) 1:1 Docetaxel + Trastuzumab + PERTUZUMAB An international phase III randomised, double-blind, placebo-controlled study (approximately 250 sites worldwide) Endpoints PFS and overall survival quality of life biomarker analysis a Actual recruitment to date = Completed

18 CLEOPATRA: Independently Assessed PFS Ptz + T + D: median 18.5 mos Pbo + T + D: median 12.4 mos (HR: 0.62; 95% CI: ; P <.001) n at risk Ptz + T + D Pbo + T + D Baselga J, et al Stratified by previous treatment status and region

19 CLEOPATRA: Response Data Patients (%) Trastuzumab + Docetaxel + Pertuzumab (n = 343) ORR: 80.2% Trastuzumab + Docetaxel + Placebo (n = 336) ORR: 69.3% CR PR SD PD Not evaluable Baselga J, et al. 2012

20 CLEOPATRA: Safety Adverse Events, % Trastuzumab + Docetaxel + Pertuzumab (n = 407) Trastuzumab + Docetaxel (n = 397) All Grades Grade 3 All Grades Grade 3 Diarrhea Alopecia 60.9 NR 60.5 NR Neutropenia Nausea 42.3 NR 41.6 NR Fatigue Rash 33.7 NR 24.2 NR Decreased appetite 29.2 NR 26.4 NR Mucosal inflammation 27.8 NR 19.9 NR Asthenia Peripheral edema 23.1 NR 30.0 NR Constipation 15.0 NR 24.9 NR Febrile neutropenia Dry skin 10.6 NR 4.3 NR Leukopenia NR 12.3 NR 14.6 Baselga J, et al. 2012

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23 Plenary Presentation Primary Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib in HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane K Blackwell, 1 D Miles, 2 L Gianni, 3 IE Krop, 4 M Welslau, 5 J Baselga, 6 M Pegram, 7 D-Y Oh, 8 V Diéras, 9 S Olsen, 10 L Fang, 10, MW Lu, 10 E Guardino, 10 S Verma 11 1 Duke Cancer Institute, Durham, NC, USA; 2 Mount Vernon Cancer Center, Northwood, UK; 3 San Raffaele Hospital, Milan, Italy; 4 Dana-Farber Cancer Institute, Boston, MA, USA; 5 Medical Office Hematology, Aschaffenburg, Germany; 6 Massachusetts General Hospital, Boston, MA, USA; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA; 8 Seoul National University College of Medicine, Seoul, Korea; 9 Institut Curie, Paris, France; 10 Genentech, Inc, South San Francisco, CA, USA; 11 Sunnybrook Odette Cancer Center, Toronto, Canada

24 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 bid D1 14 q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, # prior chemo, visceral disease Primary end points: PFS by independent review, OS, and safety

25 EMILIA: Key Characteristics N ~ months followup ~ 60% from U.S./Europe Well-balanced across arms: 16% first-line (relapsed on adjuvant Rx) 68% visceral+ 55% HR+ / 45% HR -

26 EMILIA: PFS by Independent Review Proportion progression-free Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No notable differences among clinical subsets or stratification factors

27 Overall Survival: Interim Analysis Proportion surviving % 77.0% 65.4% Median (mos) No. events Cap + Lap T-DM1 NR 94 Stratified HR=0.621 (95% CI, 0.48, 0.81) P= Efficacy stopping boundary P= or HR= % Time (mos) Similar improvements in RR and duration of response in favor of T DM1

28 Notable Adverse Events Cap + Lap T-DM1 Adverse Event All Grades Grade 3 All Grades Grade 3 Diarrhea 80% 21% 23% 1.6 Hand-foot synd 58% 16% 1% 0 Vomiting 29% 4% 19% 1% Hypokalemia 9% 4% 9% 2% Fatigue 28% 4% 35% 2% Nausea 45% 2% 39% 1% Mucositis 19% 2% 7% <1% Increased AST 9% 1% 22% 4% Increased ALT 9% 1% 17% 3% Neutropenia 9% 4% 6% 2% Anemia 8% 2% 10% 2% Platelets 2% <1% 28% 13%

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32 ER+/HER2+ MBC

33 Case A 71 year old female presents with a left sided breast mass that she had noted to be slowly increasing in size over the last 6 months. She had undergone regular mammograms until ~4 years ago when she simply stopped. On more careful questioning, she notes a 10 lb weight loss in the last year. PE reveals ~ 2.5 cm freely moveable breast mass in the upper outer quadrant of the left breast; additionally a 2 cm supraclavicular node was identified.

34 Case (cont) CT CAP and Bone scan reveals multiple lytic bone lesions in the spine, several subcentimeter nodules in both lung fields. CBC (mild anemia) and complete chemistry profile is normal. A biopsy of the breast and supraclavicular node reveals a ER strongly +/PR positive/ HER2 positive by FISH

35 Case (cont) How would you approach systemic therapy in this patient?

36 Summary 71 year old woman De novo metastastic ER/PR+/HER2+ breast cancer Disease in breast, bone, lung, nodes Weight loss but otherwise assymptomatic Treatment questions? Systemic therapy Should she have breast surgery?

37 Trastuzumab as First Line Therapy in Metastatic Breast Cancer (HO650g) Response and Outcome All 3+ FISH+ 2+ Response* 26% 35% 41% 0% R + SD (>6mo) 38% 48% Response Duration 19 mo S.D. Duration 15 mo Median Survival 24 mo *79% responders prev. adj. CT Vogel et al JCO 2002

38 ER and HER2 Crosstalk between ER and HER family members ER can upregulate HER2 and stimulate downstream signaling HER dependent phosphorylation promotes ER signaling Implication: dual ER/HER2 inhibition

39 Cross Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen IGFR GFR inhibitor Plasma membrane P P P P EGFR / HER2 AIs ER Cell survival Akt PI3-K P p90 RSK P P P SOS RAS RAF MAPK MEK P P Cytoplasm P P P ER P ER p160 CBP Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.

40 TAnDEM study design HER2-positive, HR-positive MBC (n=208) R Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose 2 mg/kg qw until disease progression Anastrozole 1 mg daily until disease progression Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation Kaufman et al, ESMO 2006 Mackey et al, SABCS 2006

41 TanDEM. Progression free survival Probability Events Median PFS 4.8 months 2.4 months 95% CI 3.7, , 4.6 p value No. at risk A + H A Months Kaufman et al, JCO 2009

42 EGF30008 Study Design Patient Population ER+ / PgR+ (HR+) Postmenopausal HER2+, HER2- or unknown Stage IIIb / IIIc, IV No prior treatment for MBC Stratification Disease sites Bone only / other sites Interval since prior adjuvant anti-estrogen therapy < 6 mo / > 6 mo or None R A N D O M I Z E Letrozole 2.5mg daily + Placebo Letrozole 2.5mg daily + Lapatinib 1500 mg daily n = 1286 pts (including n=219 HER2+)

43 Progression Free Survival: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo Hazard ratio (95% CI) 0.71 (0.53, 0.96) p-value Johnston et al, J Clin Oncol ;

44 Response Rate: HER2+ Population (N=219) % of Patients p= % 29% 15% CR PR SD 6 mo ORR CBR Let Let + Lap p= % Johnston et al, J Clin Oncol ; Johnston et al, J Clin Oncol ;

45 Clinical evidence for co-targeting of HER2 in ER+ve MBC Trial Regimen Population # pts Kaufman et al 1 Randomized, Phase III Johnston et al 3 Randomized, placebocontrolled phase III Anastrozole +/- trastuzumab Letrozole +/- lapatinib Median PFS, mo Endocrine therapy alone Endocrine therapy + anti-erbb HER HER Kaufman et al, J Clin Oncol ; , Johnston et al, J Clin Oncol ; ,

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47 Take Home Messages/Conclusions Multiple HER2 targeting agents are available with more on the horizon Treatment strategy for HER2 disease should continue to utilize HER2 agents even after progression Select pts can be considered for endocrine/her2 doublets without chemotherapy Strategies to overcome resistance to HER2 therapy are being explored