Systemic Treatment for HER-2(+) Metastatic Breast Cancer 고려대학교안암병원 종양혈액내과 박경화

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1 Systemic Treatment for HER-2(+) Metastatic Breast Cancer 고려대학교안암병원 종양혈액내과 박경화

2 Case 1 F/48 4 년전 Breast Ca (T2N2M0, ER+PR-HER2 IHC 2+) s/p BCS AC #4 (ADR cumulative dose 240 mg/m2) Paclitaxel #4 adj. RTx adj. tamoxifen 복용중

3 이환자에서다음단계로무엇을시행하시겠습니까? 1) 간조직검사 2) Chemotherapy + trastuzumab 치료 3) Primary tumor HER-2 FISH 의뢰 4) Serum FSH/E2 5) Echocardiography

4 본환자의간전이병변의조직검사 소견이다음과같을때당신의치료는? Pathology report: Invasive ductal carcinoma, metastatic ER/PR: +/- FSH: 89 IU/ml HER-2 IHC HER-2 FISH 1) Taxane + trastuzumab 2) Vinorelbine + trastuzumab 3) AI + Trastuzumab 4) AI + Lapatinib 5) Tamoxifen + trastuzumab

5 Case 2 C.C.: Morning sickness, vomiting Rt breast cancer, stage III (ER/PR/HER-2: -/-/3+) BCS and Adj Chemotherapy (AC followed by Docetaxel), RT Adjuvant Trastuzumab for 1 year completion: 1.5 year ago ECOG PS: 1, Normal organ function PET-CT: No metastasis

6 당신의치료는? 1) WBRT Taxane + trastuzumab 2) WBRT Capecitabine + Lapatinib 3) Radiosurgery only 4) Whole brain RT only 5) Palliative care only

7 Contents Introduction Re-subtyping on recurrence HER-2 Directed Monoclonal Antibody - Trastuzumab beyond - Pertuzumab - TDM-1 HER-2 Tyrosine kinase inhibitors New drugs in development CNS metastasis Conclusions

8 Tumors can be discordant on Recurrence ER PR Concordant Discordant E. Amir et al, J Clin Oncol 30:

9 Pivotal trials in mbc Monotherapy Combination chemotherapy Chemotherapy with Targeted agents breaks through the 12-month PFS barrier Herceptin + chemotherapy Avastin + chemotherapy (E2100) Docetaxel Chan 1999 Doxorubicin Chan 1999 Paclitaxel Seidman 2004 Vinorelbine Muñoz 2006 Doxorubicin + paclitaxel Jassem 2001 Docetaxel+capecitabine O Shaughnessy 2002 Gemcitabine + paclitaxel Albain 2004 FEC Zielinski 2005 Gemcitabine + vinorelbine Muñoz 2006 Epirubicin + docetaxel Pacilio 2006 Herceptin + docetaxel Pacilio 2006 Avastin + paclitaxel E Paclitaxel E Median PFS / TTP 12 months Time (months)

10 HER-2 Directed Treatment Saves Life HR(-) HR(+) Luminal TNBC JCO January 1, 2010 vol. 28 no

11 Targeting HER-2 Pertuzumab Trastuzumab Neratinib Lapatinib T-DM1

12 Paclitaxel/Trsatuzumab in HER-2(+) MBC Patients who received Adjuvant Chemotherapy HER-2 (+) Paclitaxel +/- Trastuzumab Paclitaxel + trastuzumab Paclitaxel 6.9 m 3.0 m Months Slamon D et al, NEJM 2001

13 What is the best partner of Trastuzumab? Combination Index (CI) scores for in-vitro activity in HER2+ breast cancer cell lines Synergistic (CI <1) Additive (CI = 1) Antagonistic (CI >1) Vinorelbine 0.34 Doxorubicin Methotrexate 1.36 Docetaxel/carboplatin 0.34 Paclitaxel 0.91 Gemcitabine (0.57) Docetaxel 0.41 Epirubicin 0.99 Fluorouracil 2.87 Etoposide 0.54 Vinblastine 1.09 Cyclophosphamide 0.57 Paclitaxel/carboplatin 0.64 Thiotepa 0.67 Cisplatin 0.67 Liposomal doxorubicin 0.70 Pegram M, et al. Oncogene. 1999;18: Pietras RJ, et al. Oncogene. 1998;17: , Bunn et al. Clin Cancer Res, 2001

14 TAnDEM: Trastuzumab plus Anastrozole HER2-positive, HR-positive Post-menopausal MBC (n=208) R Anastrozole 1mg daily until disease progression Anastrozole 1mg daily + Trastuzumab 4mg/kg loading 2mg/kg qw until disease progression JCO November 20, 2009 vol. 27 no

15 Efficacy PFS OS JCO November 20, 2009 vol. 27 no

16 Trastuzumab beyond Progression HER-2(+) MBC Progression on Trastuzumab (n=156) 1:1 R Capecitabine Trastuzumab + Capecitabine mttp: 5.6 M vs 8.2 M, [HR], 0.69 P=.0338 mos: 20.4 M vs 25.5 M, [HR], 0.76 P=.257 JCO April 20, 2009 vol. 27 no

17 Mechanisms of Trastuzumab Resistance Low PTEN expression Increased Akt activity Activation of lateral signaling pathways IGF-IR overexpression Met overexpression TGF-α overexpression Steric hindrance blocking Trastuzumab binding Increased level of MUC4 Presence of truncated forms of HER-2 Impaired ADCC

18 Monoclonal Antibodies Trastuzumab (HER2) Pertuzumab (HER2) T-DM1 (HER2) Cixutumumab (IGF1R) Bevacizumab (VEGF) Tyrosine Kinase Inhibitors Lapatinib (HER1, 2) Neratinib (HER1,2,4) Afatinib (HER1,2,4) BMS (IGF1R) Sunitinib (VEGF, PDGFR, C-KIT) Pazopanib (VEGF, PDGFR, C-KIT) Tanespimycin Retaspimycin AUY922 Inhibition of downstream targets Everolimus (mtor) BKM120 (PI3K/Akt) BEZ-235 (PI3K/Akt/mTOR) hsp90 Br J Cancer Jan 3;106(1):6-13

19 New HER-2 Targeted Monoclonal Antibodies. Trastuzumab Pertuzumab T-DM1

20 Pertuzumab : Targets Different Domain of HER-2 Pertuzumab Herceptin Activates antibody-dependent cellular cytotoxicity Inhibits HER2-mediated signalling Inhibits shedding and, thus, formation of new p95 Inhibits HER2-related angiogenesis Activates antibody-dependent cellular cytotoxicity Prevents receptor dimerisation Potent inhibitor of HER2/HER2- and HER2/HER3-mediated signalling pathways Hubbard 2005

21 NEOSPHERE Neoadjuvant treatment Adjuvant treatment n=417 a Herceptin Docetaxel Herceptin Pertuzumab Docetaxel Herceptin Pertuzumab Pertuzumab Docetaxel q3wks x 4 q3wks x 4 q3wks x 4 q3wks x 4 S U R G E R Y Herceptin q3wks until cycle 17** FEC x 3 q3wks FEC x 3 q3wks Docetaxel 75 C1 then 100 x 3 cycles FEC x 3 q3wks FEC x 3 q3wks Endpoints partial clinical response at point of surgery biomarker analysis

22 NeoSphere pcr rates: ITT Population Summary p = p = p = pcr, % ± 95% CI TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L, 2010 SABCS

23 NeoSphere: pcr and HR Status pcr, % ± 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel ER or PR pos ER and PR neg TH THP HP TP Gianni L, 2010 SABCS

24 BO17929: Phase II trial of Pertuzumab and Herceptin (HER2+ progressing on Herceptin) Simon-type 2-stage design Stage 1 (n=24) Herceptin + Pertuzumab 2 responses or 1 response + 12 SD or 13 SD Safety evaluation for IDSMB Following completion of recruitment into Stage 2 Yes No Stage 2 (n=66) 50% Stop trial Stage 3 (n=27) Pertuzumab Response required 11% Documented progression Herceptin + pertuzumab or alternative therapy Primary objectives Safety and efficacy (response rate + stabilisation of disease = CBR) 27% Baselga et al 2007

25 Efficacy J Clin Oncol 2010, 28:

26 Safety J Clin Oncol 2010, 28:

27 CLEOPATRA: Pertuzumab plus Trastuzumab plus Docetaxel for MBC HER-2(+) MBC (n=800) 1:1 R Trastuzumab + Docetaxel + Placebo Trastuzumab + Docetaxel + Pertuzumab Primary endpoint: PFS Secondary endpoints: OS, Quality of life, Biomarker analysis Baselga J, N Engl J Med 2012;366:

28 Baselga J, N Engl J Med 2012;366:

29 PFS Pertuzumab: 18.5 mo Control: 12.4 mo OS HR: 0.62 (95%CI: ), P<0.001 HR: 0.64 (95%CI: ), P=0.005 Response Placebo + Trastuzumab Pertuzumab + Trastuzumab Number (%) Objective response 233 (69.3) 275 (80.2) Complete response 14 (4.2) 19 (5.5) Partial response 219 (65.2) 256 (74.6) Stable disease 70 (20.8) 50 (14.6) Progressive disease 28 (8.3) 13 (3.8) Not assessable 2 (0.6) 2 (0.6) No assessment performed 3 (0.9) 3 (0.9) Baselga J, N Engl J Med 2012;366:

30 Adverse Events Placebo+ Doc+Trastzmab Pertuzumab+ Doc+Trastzmab Most common events, all grades G3 or higher events Baselga J, N Engl J Med 2012;366:

31 T-DM1: A New Concept Drug Clin Cancer Res; 17(20) October 15, 2011

32 Efficacy from Phase I/II Trials Clin Cancer Res; 17(20) October 15, 2011

33 Selected Adverse Events: Studies TDM4374g & TDM4258g* TDM4374g n=110 TDM4258g n=112 Selected AE Category All Grades Grade 3 All Grades Grade 3 Anemia 18.2% 1.8% 20.5% 2.7% Cardiac disorders 1.8% 0% 2.7% 0% Eye disorders 20.0% 0% 31.3% 0.9% GI toxicity 58.2% 2.7% 75.0% 0.9% Hemorrhage 22.7% 0.9% 45.5% 5.4% Hepatic dysfunction 30.0% 8.2% 13.4% 5.4% Hypokalemia 19.1% 1.8% 26.8% 8.9% Infusion reactions* 11.8% 0% 8.0% 0.9% Leukopenia 10% 0% 8.9% 2.7% Peripheral neuropathy 9.1% 0% 20.5% 0.9% Pulmonary disorders 3.6% 2.7% 2.7% 0.9% Thrombocytopenia 33.6% 7.3% 18.8% 8.9% *TDM4258g; single-agent T-DM1 (3.6 mg/kg i.v. q3w) for HER2-positive MBC patients who have progressed on HER2 therapy and who have previously received trastuzumab and 1 line of chemotherapy for MBC 33

34 Putting the T-DM1 data into context T-DM1 studies BO g 1 n= g 2 n=110 Herceptin + pertuzumab n=66 X+L 4 n=198 L 5 n=366 H+L 6 n=148 Neratinib 7 n=61 H and lapatinib pretreated Yes (subgroup) Yes NO NO NO NO NO Prior lines / (n chemoagents) NA (median 3 agents used) NA (median 8 agents used) median 5 1 ORR 24% 8 33% 8 24% 8 24% 1-7% 10% 26% CBR 36% 8 45% 8 50% 8 29% 6-12% 25% 36% PFS [months] na ~2 2.8 na Duration of response [months] na Not reached na na na 1 Vogel et al, ASCO 2009; 2 Krop et al, SABCS 2009; 3 Gelmon et al, ASCO 2008; 4 Cameron et al, BRT 2008; 5 3 studies combined: Burstein et al, Annals 2008; Blackwell et al, ASCO 2004; O Shaughnessy et al ASCO 2008; 6 O Shaughnessy et al ASCO 2008; 7 Burstein et al SABCS 2008; 8 independent review / ITT, X = Xeloda, L = lapatinib, H = Herceptin, ORR = Objective Response Rate, CBR = Clinical Benefit rate, PFS = progression free survival,

35 Primary Results From EMILIA Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib in HER2(+) 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 2012 ASCO annual meeting

36 EMILIA Study Design HER-2(+) MBC Previous TrastzM/Taxane (n=580) R Lapatinib/Capecitabine TDM mg/kg q3w IV * Stratification factors: - World region, - # of prior chemo regimens for MBC or unresectable LABC - Presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of res ponse, time to symptom progression K Blackwell et al, 2012 ASCO annual meeting

37 Prior Systemic Treatment Prior treatment type, n (%) Taxanes Anthracyclines Endocrine agents Prior therapy for MBC, n (%) Yes No Prior trastuzumab treatment, n (%) EBC only Duration of trastuzumab treatment, n (%) <1 yr 1 yr Cap + Lap (n=496) 494 (100) 302 (61) 204 (41) 438 (88) 58 (12) 495 (100) 77 (16) 212 (43) 284 (57) T-DM1 (n=495) 493 (100) 303 (61) 205 (41) 435 (88) 60 (12) 495 (100) 78 (16) 210 (42) 285 (58) Median time since last trastuzumab, mos (range) 1.5 (0 98) 1.5 (0 63) K Blackwell et al, 2012 ASCO annual meeting

38 Drug Exposure Cap (n=487) Lap (n=488) T-DM1 (n=490) Median dose intensity, % Pts with dose reduction, n (%) 260 (53.4) 133 (27.3) 80 (16.3) T-DM1 decreased to 3.0 mg/kg, n (%) 58 (11.8) T-DM1 decreased to 2.4 mg/kg, n (%) 22 (4.5) K Blackwell et al, 2012 ASCO annual meeting

39 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. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). K Blackwell et al, 2012 ASCO annual meeting

40 Progression-Free Survival by Independent (IRC) and Investigator (INV) Review Proportion progression-free IRC INV Cap + Lap T-DM1 Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P< HR=0.658 (95% CI, 0.56, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR by independent review=0.66 (P<0.0001). K Blackwell et al, 2012 ASCO annual meeting

41 Overall Survival: Interim Analysis Proportion surviving % 77.0% 65.4% 47.5% 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) No. at risk: Cap + Lap T-DM Unstratified HR=0.63 (P=0.0005). NR=not reached. K Blackwell et al, 2012 ASCO annual meeting

42 ORR and Duration of Response (DOR) in Patients with Measurable Disease Percent ORR Difference: 12.7% (95% CI, 6.0, 19.4) P= % 120/389 Cap + Lap 43.6% 173/397 T-DM1 Proportion progression-free DOR Median, mos (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) No. at risk Cap + Lap T-DM K Blackwell et al, 2012 ASCO annual meeting

43 Non-Hematologic Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Hypokalemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT K Blackwell et al, 2012 ASCO annual meeting

44 Hematologic Adverse Events Adverse Event All Grade, % Cap + Lap (n=488) Grade 3, % Grade 4, % All Grade, % T-DM1 (n=490) Grade 3, % Grade 4, % Neutropenia Febrile neutropenia Anemia Thrombocytopenia K Blackwell et al, 2012 ASCO annual meeting

45 Phase II Trial: TDM1 vs Trastuzumab/Docetaxel as First-Line Therapy for HER2+ MBC PFS by Investigator Hurvitz SA, et al. Abstract ESMO 2011.

46 Coming soon... Marianne HER-2(+) MBC Previous untreated (n=1092) R Trastuzumab + Weekly Paclitaxel Or 3-weekly Docetaxel TDM-1 TDM-1/Pertuzumab

47 AVEREL: Trastuzumab/Docetaxel ± Bevacizumab in HER-2(+) MBC HER-2(+) MBC (n=424) 1:1 R Trastuzumab + Docetaxel + Placebo Trastuzumab + Docetaxel + Bevazumab Primary endpoint: investigator assessed PFS Gianni et al, 2011 SABCS

48 Historical Timeline : Treatment of HER-2(+) MBC Rugo H, 2011 SABCS

49 Investigator-Assessed PFS According to Baseline Plasma VEGF-A *Baseline VEGF was collected in 40% of patients. Gianni, 2011 SABCS

50 HER-2(+) Directed TKIs

51 Lapatinib Oral, small-molecule, dual-targeted agent

52 EGF Study Design HER-2(+) Locally advanced or MBC progressed after prior anthracycline, taxane and trastuzumab (N=399) RANDOMISATION Tykerb 1250 mg PO/d continuously + Capecitabine 2000 mg/m 2 /D po D 1-14 q 3 wk Capecitabine 2500 mg/m 2 /day po D 1-14 q 3 wk Treatment continued until progression or unacceptable toxicity po = oral; od = once daily; q 3 wk = once every 3 weeks Geyer GE et al. N Engl J Med 2006

53 Survival Outcome PFS OS PFS: 8.4 m vs 4.4m Geyer GE et al. N Engl J Med 2006

54 Cutaneous Effects of EGFR Inhibitors EGFR expression in skin - basal keratinocytes - sebocytes - outer root sheath - some endothelial cells Abnormal scalp, face hair, and/or eyelash growth Papulopustular eruption (PPE) Paronychia ± pyogenic granulomas Telangiectasias Xerosis

55 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) Adverse event Grade Nail changes Discolouration; ridging (koilonychias); pitting Partial or complete loss of nail(s); pain in nail bed(s) Interfering with ADL Rash Macular or papular eruption or erythema without associated symptoms Macular or papular eruption or erythema with pruritis or other associated symptoms; localized desquamation or other lesions covering <50% of the body surface area (BSA) Severe, generalized erytheroderma or macular, papular or vesicular eruption; desquamation covering 50% BSA Generalized exfoliative ulceritive or bullous dermatitis Death

56 Examples of Paronychia Grade 1 Discoloration Ridging (koilonychias) Pitting Grade 2 Partial or complete loss of nail(s) Pain in nailbed(s) Grade 3 Interfere with ADL Breast Cancer Res Treat (2009) 114:

57 Management of Skin Events Pruritus Cool compresses, sedating antihistamine at evening/bedtime, topical steroids, topical menthol lotions Gabapentin or pregabalin Bacterial and fungal culture, systemic antibiotics Paronychia Monsel s solution, zinc oxide cream Soaks with 4% thymol in alcohol, white vinegar, bleach Topical steroids for noninfected paronychia Nail clipping or possible removal of nail plate Petroleum jelly (Vaseline), thick emollients Desquamation Fissuring Mild neutral ph soap Keratinolytics (ammonium lactate, 6% salicylic acid, 20% urea) Monsel s solution, Zinc oxide Protective coverings, cyanoacrylate glue to fissures to relieve pain and promote healing NCCN Task force report, JNCCN Vol 7, May 2009

58 Lapatinib/Letrozole in HR(+) MBC HR(+) MBC (n=1286) HER-2(+) MBC (n=219) HER-2(-) MBC (n=952) HER-2(?) MBC (n=115) R R R Lapatinib + Letrozole Letrozole Lapatinib + Letrozole Letrozole Lapatinib + Letrozole Letrozole JCO November 20, 2009 vol. 27 no

59 Efficacy: Overall Population JCO November 20, 2009 vol. 27 no

60 Clinical Efficacy in HER-2(+) Patients PFS: 8.2 m vs 3.0m

61 HER-2 (-) HER-2 (-) with Tamoxifen failure in 6M

62 PI3K/Akt/mTOR Inhibitors PI3K

63 Everolimus & Trastuzumab : Phase I/II Study Eligibility: Progression on Trastuzumab Treatment: Everolimus 5 or 10mg + 3 Weekly Trastuzumab 6mg/kg Endpoints: - Primary: Optimal dose, Efficacy, Safety - Secondary: PTEN, Akt, p70s6, Src protein expression, PIK3CA mutations JCO August 10, 2011 vol. 29 no

64 Effect of PTEN Combined Effect of PTEN loss & PI3K Mutation PRs: 15%, psd: 19%, CBR of 34% First line treatment using Everolimus, Trastuzumab, Paclitaxel is being tested. JCO August 10, 2011 vol. 29 no

65 HSP90 Inhibitors Client Proteins: HER2, EGFR, nuclear steroid receptors, RAF-1, CDK4, AKT, MET, and HIF-1a. Clin Cancer Res; 17(15) August 1, 2011

66 Phase II Trial of Tanespimycin/Trastuzumab in HER2(+) MBC Progressing on Trastuzumab N=31 Treatment: Tanespimycin (KOS-953) 450 mg/ m2 + Trastuzumab Weekly Toxicity: diarrhea, nausea, headache, fatigue, and neuropathy (mostly grade 1 to 2). Clin Cancer Res; 17(15) August 1, 2011

67 Efficacy Best Overall tumor response, n(%) N=27 95% CI Response rate 22% CR 0 PR 6 (22%) SD 10 (37%) PD 11 (41%) Clinical benefit 59% mpfs 6 month 4-9 mos 17 month Clin Cancer Res; 17(15) August 1, 2011

68 Brain metastasis in HER-2(+) Breast Cancer Incidence in Advanced breast cancer; 14-16% Risk factors; HER-2(+), TNBC (46% in lifetime) BM in Trastuzumab treated HER-2(+) pts; ~50% 50% of BM occurs while extra-cns disease is under control Trastuzumab poorly penetrates intact BBB.

69 Current Management of MBC in CNS Multidisciplinary management of brain metastases. Oncologist 12: , 2007

70 Adjuvant Trastuzumab 이 BM 를조장하는가? Breast Cancer Res Treat (2008) 109: NSABP B-31 NCCTG N9831 HERA Trastuzumab 3.24% 1.49% 1.53% Non-Trastuzumab 4.0% 0.5% 1.3% P-value ns ns ns

71 BM in Trastuzumab Treated Patients for MBC J Clin Oncol 27:

72 Trastuzumab Improves Patients with HER-2(+) BC in CNS Time to BM Time to Death with BM British Journal of Cancer (2009) 100(6), J Clin Oncol 27:

73 Lapatinib in HER-2(+) BM Lapatinib Single Extended Lapatinib/Capecitabine

74 Trastuzumab beyond BM Overall Survival after BM Time to brain progression after BM Park IH et al, Ann Oncol (2009) 20 (1):

75 Trastuzumab Penetrates Impaired BBB Dijkers ECF, Clinical Pharmacology & Therapeutics (2010)

76 Conclusions Additional Targeting HER-2 using improves PFS in metastatic breast cancer patients.: Pertuzumab, Bevacizumab New concept of HER-2 targeted antibody has promising efficacy and safety profile: T-DM1 Targeting PI3K/mTOR or hsp90 has promising early clinical data. Trastuzumab and lapatinib improves prognosis of HER- 2(+) MBC patients even in BM cases.

77 Research Cures Cancer!