Her 2 Positive Advanced Breast Cancer: From Evidence to Practice

Her 2 Positive Advanced Breast Cancer: From Evidence to Practice Sunil Verma MD, FRCP(C) Medical Director, Tom Baker Cancer Center Professor and Head, Department of Oncology Cumming School of Medicine, University of Calgary, Canada Department of Oncology University of Calgary

Disclosures Advisory Board: Amgen, Astra Zeneca, BI, BMS, Eisai, Merrimack, Novartis, Pfizer, Roche, Spectrum

Clinical Management of Her 2+ Metastatic Breast Cancer Giordano et al. JCO 2014 (ASCO GUIDELINES)

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Trastuzumab prolongs overall survival in HER2-positive MBC 100 Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) Overall survival (%) 80 60 40 20 Median OS: 20.3 months RR = 0.80 (95% CI = 0.64,1.00) p = 0.046 Median OS: 25.1 months 0 0 5 15 25 35 45 Time (months after enrolment) OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel OS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783 792.

Recent Trials in First Line Her 2 positive MBC First Line MA.31 Taxane + Trastuzumab vs. Taxane + Lapatinib NEFERT-T Taxane + Trastuzumab vs. Taxane + Neratinib BOLERO-1 Paclitaxel + Trastuzumab vs. Paclitaxel + Trastuzumab + Everolimus CLEOPATRA Docetaxel + Trastuzumab vs. Docetaxel + Trastuzumab + Pertuzumab MARIANNE Docetaxel/Paclitaxel + Trastuzumab vs. T-DM1 vs. T-DM1 + Pertuzumab PERUSE Taxane + Trastuzumab + Pertuzumab 7

1 st line Pertuzumab + Trastuzumab (CLEOPATRA) HER2+ (central) LABC or MBC (N=808) 1:1 n=402 Pertuzumab+trastuzumab (840 mg 420 mg q3wks) Docetaxel 6 cycles PD 1 year from completion of adjuvant trastuzumab n=406 Placebo+trastuzumab (8 mg/kg 6 mg/kg q3wks) Docetaxel 6 cycles PD Important points: ~ 90% of patients did not receive trastuzumab in (neo) adjuvant setting ~ 50% of patients did not receive any prior (neo) adjuvant chemotherapy Patients with CNS metastases were excluded Baselga et al. N Engl J Med 2012;366:109. 8

1st-line Pertuzumab + Trastuzumab (CLEOPATRA) Progression-free survival 1 Overall survival 2 Progression-free survival (%) 100 90 80 70 60 50 40 30 20 10 0 Pertuzumab+trastuzumab+ docetaxel Placebo+trastuzumab+docetaxel 0 10 20 30 40 50 60 70 80 Time (months) OS (%) 100 90 80 70 60 50 40 30 20 10 0 Pertuzumab+trastuzumab+ docetaxel Placebo+trastuzumab+docetaxel 0 10 20 30 40 Time (months) 50 60 70 80 Pertuzumab+ trastuzumab+docetaxel Placebo+ trastuzumab+docetaxel Hazard ratio P-value ORR 1 80.2% 69.3% 0.0001 PFS 1 18.7 months 12.4 months 0.69 <0.0001 OS 2 56.5 months 40.8 months 0.66 0.0001 Most common adverse events Grade 3 in the pertuzumab+trastuzumab+docetaxel group: 1 Neutropenia (48.9%), febrile neutropenia (13.8%), leukopenia (12.3%) and diarrhoea (7.9%) Median follow-up: 30 months. PFS, progression-free survival; OS, overall survival. 1. Baselga et al. N Engl J Med 2012;366:109; 2. Swain et al. NEJM 2015;724:734. 9

Cleopatra Overall Survival Cross over patients (11%) excluded Swain et. al NEJM 2015

MARIANNE: Phase III study of T-DM1 with or without Pertuzumab vs Taxane and Trastuzumab (no Pertuzumab) HER2-positive progressive or recurrent locally advanced BC or previously untreated MBC (n=1092) R Trastuzumab + taxane (n=364) T-DM1 + pertuzumab (n=364) T-DM1 + placebo (n=364) Trastuzumab + Taxane T-DM1 + Placebo Ellis et al ASCO 2015, Breast Cancer Oral Session Monday June 1, 2015 T-DM1 + Pertuzumab Hazard ratio ORR 67.9% 59.7% 64.2% NR NR PFS 13.7 m 14.1m 15.2m HR 0.91 HR 0.87 OS 50.9 53.7 51.8 HR 0.93 HR P-value p=0.31 p=0.14 P NS p NS 11

MARIANNE Trial Progression Free Survival Perez E et al, JCO 2016

Final Analysis of Overall Survival Presented By Edith Perez at 2017 ASCO Annual Meeting

Anti-Cancer Therapy During Follow-Up Presented By Edith Perez at 2017 ASCO Annual Meeting

PERUSE: 1L pertuzumab and trastuzumab with taxane therapy in HER2-positive labc or mbc PERUSE tests the safety and efficacy of pertuzumab and trastuzumab when combined with investigator s choice of taxane in 1L HER2-positive mbc The study is a post-approval measure for the EMA to support the label in Europe It expands on the information obtained from CLEOPATRA by providing safety and efficacy data for combination of PH with taxanes other than docetaxel Phase IIIb study design: Male or female patients with HER2-positive mbc (N = 1436) Primary endpoint: Safety, tolerability Secondary objectives: PFS, OS, BOR Pertuzumab + trastuzumab + taxane* (docetaxel or paclitaxel or nab-paclitaxel) * Investigator s choice of taxane * Investigator s choice of taxane T Bachelot, et al. Poster presentation, Abstract P4-21-04 SABCS 2016

PERUSE preliminary data: Efficacy Median follow-up: 17.2 months Progression-free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 ITT population by taxane Total Censored Event s Median (95% CI) Docetaxel 775 333 (43.0%) 442 19.71 (17.45, 22.87) Paclitaxel 589 261 (44.3%) 328 24.67 (20.67, 26.25) Nabpaclitaxel 65 25 (38.5%) 40 18.07 (12.22, 34.23) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 n at risk Months Docetaxel 775 751 721 672 603 544 485 439 406 373 327 280 235 204 161 118 87 67 39 18 12 8 3 0 Paclitaxel 589 574 557 524 473 429 395 365 338 315 290 264 222 184 149 124 93 75 41 27 11 1 0 0 Nab-paclitaxel 65 63 60 55 47 43 40 36 34 32 28 27 26 24 23 19 15 10 3 2 1 1 0 0 Median PFS = 21.2 months in all patients who received at least one dose of study treatment

Summary First Line The standard of care should consist of pertuzumab and trastuzumab along with a taxane T-DM1 looks very promising in the first line and may be suited for selected patients Not candidates for chemotherapy DFI < 6 months Contraindication to taxanes? Previous (neo) adjuvant Pertuzumab 17

Future Questions First Line Duration of targeted therapy for those responding Duration of chemotherapy when receiving dual targeted therapy Combination of endocrine therapy with dual targeted anti-her 2 tx for ER+/Her 2 +ve pts (PERTAIN) 18

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Prior exposure to trastuzumab (adj +/- metastatic) Comparison of patient populations EMILIA (NEJM 2012) BOLERO 3 (ASCO 2014) LUX Breast (SABCS 2014) TH3RESA (Lancet Oncol 2014) EGF 104900 (JCO 2012) Control Capecitabine + Lapatinib Vinorelbine + Trastuzumab Vinorelbine + Trastuzumab Physician s choice Lapatinib alone Experimental T-DM1 Vinorelbine + Trastuzumab + Everolimus Vinorelbine + Afatinib T-DM1 Lapatinib + Trastuzumab Prior anti-her2 with relapse < 1 year Prior anti-her2 with relapse on therapy Yes Yes Yes Yes Yes Yes Previous TRAS and Taxane Adapted from M. Piccart St. Gallen 2015 Presentation Yes Mean of 1.6 lines of previous trastuzumab regimens Yes 1 previous TRAS regimen Yes Median of 4 regimens for advanced breast cancer Yes Median of 3 previous trastuzumab regimens for metastatic

T-DM1 vs. Capecitabine and Lapatinib (EMILIA) HER2-positive (central) LABC or MBC (N=980) n=495 T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic therapy or within 6 months of adjuvant therapy 1:1 n=496 Lapatinib 1250 mg/day orally qd Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w PD Primary endpoint: independently assessed PFS, OS, safety Key secondary endpoints: investigator-assessed PFS, ORR LABC, locally advanced breast cancer; MBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; IV, intravenous; PD, progressive disease; qd, once daily; bid, twice daily; PFS, progression-free survival; OS, overall survival; ORR, objective response rate. Verma et al. N Engl J Med 2012;367:1783. 21

EMILIA Results Progression-free survival Overall survival Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 T-DM1 Lapatinib+capecitabine 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (months) Proportion surviving 1.0 0.8 0.6 0.4 0.2 85.2% 78.4% 64.7% 51.8% T-DM1 Lapatinib+capecitabine 0.0 0 2 4 6 8 10 1214 16 18 20 2224 26 28 3032 34 36 Time (months) T-DM1 Lapatinib+capecitabine Hazard ratio P-value PFS 9.6 months 6.4 months 0.65 <0.001 OS 30.9 months 25.1 months 0.68 <0.001 Most common adverse events Grade 3: T-DM1: thrombocytopenia (12.9%) and transaminitis (4.3%) Lapatinib+capecitabine: diarrhoea (20.7%) and hand foot syndrome (16.4%) PFS, progression-free survival; OS, overall survival; T-DM1, trastuzumab emtansine. Verma et al. N Engl J Med 2012;367:1783. 22

T-DM1 vs. Physician Tx of Choice (TH3ERESA) HER2-positive (central) advanced breast cancer (N=602) n=404 T-DM1 3.6 mg/kg q3w IV PD 2 prior HER2-directed therapies for advanced BC 2:1 Prior treatment with trastuzumab, lapatinib, taxane n=198 Physician s choice PD T-DM1 (optional crossover) Primary endpoint: investigator evaluated PFS and OS Key secondary endpoints: ORR and safety *Physician s choice could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2- directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. BC, breast cancer; T-DM1, trastuzumab emtansine; IV, intravenous; PD, progressive disease; PFS, progression-free survival; OS, overall survival; ORR, overall response rate. Krop IE et al. Lancet Oncol 2014; 15: 689 99. 23

TH3RESA interim results PFS by investigator assessment First interim OS analysis Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 0 2 T-DM1 Physicians choice 4 6 8 10 12 14 Time (months) Proportion surviving 1.0 0.8 0.6 0.4 0.2 0.0 Observed 21% of targeted events T-DM1 Physicians choice 0 2 4 6 8 10 12 14 16 Time (months) T-DM1 Physicians choice * Hazard ratio P-value PFS 6.2 months 3.3 months 0.53 <0.0001 OS (immature) NE 14.9 months 0.55 0.0034 (NS) T-DM1, trastuzumab emtansine; PFS, progression-free survival; OS, overall survival; NE, not evaluable. *68.5% chemo + T. 10.3% T + L. 2.7% chemo + L Krop IE et al. Lancet Oncol 2014; 15: 689 99. 24

TH3RESA SABCS 2015 Update Weilders et al SABCS 2015 25

PHEREXA: A clinical trial of pertuzumab in second-line metastatic breast cancer Arm A: Pertuzumab + trastuzumab + capecitabine HER2-positive MBC (N = 450) R Arm B: Trastuzumab + capecitabine 2013 2014 Last patient in Q3

PHREXA Summary Primary Endpoint Progression Free Survival (Independent Review) Progression Free Survival (Investigator) Overall Survival Capecitabine+Trast uzumab Capecitabine+Tras tuzumab+pertuzu mab HR p-value 9.0 m 11.1 m 0.82 (0.65-1.02) p=0.07 9.0 11.8 0.81 P=0.05 28.1 m 36.1 m 0.68 NE Toxicity: Increased rates of Grade 3 and greater toxicity with Cape+Tras+Pert: Diarrhea, LVSD

Pertuzumab for Advanced Breast Cancer PHREXA and CLEOPATRA Capecitabine +Trastuzuma b Capecitabine+ Trastuzumab+ Pertuzumab HR p-value Docetaxel + Trastuzuma b +Placebo Docetaxel + Trastuzumab +Pertuzumab HR p-value Primar y Endpoi nt PFS (Indepe ndrevi ew) 9.0 m 11.1 m 0.82 (0.65-1.02) p=0.0 7 12.4 m 18.7 m 0.69 p<0.000 1 Overall Surviv al 28.1 m 36.1 m 0.68 NE 40.8 m 56.5 m 0.66 p=0.000 1 Presented by Sunil Verma, MD Swain et. al NEJM 2015

T-DM1 Post Pertuzumab Data from CLEOPATRA and PHREXA Studies

T-DM1 Post Pertuzumab Data from CLEOPATRA and PHREXA Studies

T-DM1 Post Pertuzumab Data from CLEOPATRA and PHREXA Studies

Response Rate Median Duration of Treatment : 4.0 months 35% of patients had treatment beyond six months post Pertuzumab

Her 2 Positive Metastatic Breast Cancer Significant gains in Survival

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Individualized Approach Prior adjuvant therapy Hormone Receptor Status

Her 2 Positive Metastatic Breast Cancer Key Clinical Scenarios Presents with de novo metastasis No previous TRAS Develops metastasis following adjuvant therapy Adjuvant without TRAS TRAS-free Interval 1yr Adjuvant TRAS < 1yr Different sensitivities to anti-her2 drugs? Adapted from M. Piccart St. Gallen 2015 Presentation 36

Comparison of patient populations Limited prior Adjuvant Trastuzumab Therapy MARIANNE (ASCO 2015) CLEOPATRA (NEJM 2015) BOLERO-1 (SABCS 2014) MA-31 (ASCO 2012) Chemo Docetaxel/Pacl itaxel Docetaxel Paclitaxel Taxane Anti-HER2 regimens tested T-DM1 or T-DM1 + Pertuzumab Trastuzumab + Pertuzumab (vs TRAS) Trastuzumab + Everolimus 10mg OD (vs TRAS) Lapatinib (vs TRAS) De novo metastatic Prior adj. trast. (and interval >1y) 55% 53% 50% 43% 31% 11% 10% 18% The results of most of these trials are relevant today only for de novo metastatic patients Adapted from M. Piccart St. Gallen 2015 Presentation

Prior Trastuzumab Efficacy Data Adjuvant Trastuzumab DFI > 1year MARIANNE (ASCO 2015) CLEOPATRA (NEJM 2015) 1 BOLERO1 (SABCS 2014) MA-31 (ASCO 2012) PFS 10.3 months vs 15.2 months (T-DM1) 10.4 months vs. 16.9 months (p value not reported) NR NR OS 40.8 months vs 52.3 months (p=ns) 46.6 months vs 53. 8 months (p value not reported) NR NR 1 Swain et al NEJM Correspondence 2015

T-DM1 and PFS: effect of prior therapies Presented By Paul Ellis at 2015 ASCO Annual Meeting

OS Subgroup Analyses by Baseline Risk Factors <br />T-DM1 vs HTa Presented By Carlos Barrios at 2017 ASCO Annual Meeting

Response to T-DM1 lasts longer Presented By Paul Ellis at 2015 ASCO Annual Meeting

EMILIA: Progression-Free Survival Subgroup Analyses Cap + Lap T-DM1 Baseline characteristic All pts Total n 991 Median, mos 6.4 Median, mos HR (95% CI) 9.6 0.66 (0.56, 0.78) Prior Trastuzumab T-DM1 better Cap + Lap better Age <65 yrs 65 yrs 853 138 6.0 8.1 9.8 7.0 0.62 (0.52, 0.74) 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR 545 426 7.1 5.6 9.0 10.3 0.72 (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third 118 361 512 5.7 6.8 6.5 10.8 9.6 9.0 0.51 (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) Data cut-off Jan 14, 2012 HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy. Hazard ratio 0.2 0.5 1 2 5 Verma et al. N Eng J Med 2012 (incl. supplementary appendix) Blackwell et al. ASCO 2012; Abst #LBA1

Prior Trastuzumab EMILIA: Overall Cap + Lap Survival T-DM1 Subgroup Analyses Baseline Total Median Median HR T-DM1 Cap + Lap characteristic n (mos) (mos) (95% CI) Better Better All patients 991 25.1 30.9 0.70 (0.56, 0.87) Age group <65 years 853 24.6 30.9 0.66 (0.52, 0.83) 65 74 years 113 27.1 NR 0.74 (0.37, 1.47) 75 years 25 NR 11.1 3.45 (0.94, 12.65) ER and PR status ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85) ER and PR 426 23.7 27.1 0.75 (0.54, 1.03) Line of therapy a First-line 118 27.9 NR 0.61 (0.32, 1.16) Second-line 361 NR 27.1 0.88 (0.61, 1.27) Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84) Hazard ratio 0.2 0.5 1 2 5 a Defined as any systemic therapy including endocrine and chemotherapy. NR, not reached. From confirmatory OS analysis; data cut-off July 31, 2012. Verma et al. ESMO 2012; Oral Abstract #LBA12

CLEOPATRA PFS in predefined subgroups Prior (neo)adjuvant chemotherapy Region Age group Race All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other Favors pertuzumab Favors placebo Hormone Receptor Status n HR 95% CI 808 0.69 0.58 0.81 432 0.67 0.54 0.85 376 0.70 0.55 0.90 306 0.70 0.53 0.91 135 0.60 0.40 0.91 114 0.54 0.34 0.85 253 0.81 0.60 1.10 681 0.72 0.60 0.87 127 0.49 0.31 0.76 789 0.69 0.59 0.82 19 0.62 0.16 2.40 480 0.65 0.52 0.80 30 0.50 0.16 1.54 261 0.81 0.60 1.10 37 0.47 0.20 1.10 Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative IHC 3+ FISH-positive 630 0.63 0.53 0.76 178 0.89 0.61 1.31 388 0.76 0.60 0.97 408 0.62 0.49 0.78 721 0.66 0.55 0.79 767 0.70 0.59 0.83 0 1 2 3 ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PFS, progression-free survival; PgR, progesterone receptor 44 Swain et al. SABCS 2012 Poster P5-18-26.

CLEOPATRA Overall survival in predefined subgroups Favors pertuzumab Favors placebo Hormone Receptor Status n HR 95% CI Prior (neo)adjuvant chemotherapy Region Age group Race All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other 808 0.66 0.52 0.84 432 0.66 0.47 0.93 376 0.66 0.46 0.94 306 0.72 0.48 1.07 135 0.68 0.36 1.28 114 0.55 0.31 0.98 253 0.64 0.41 1.00 681 0.70 0.53 0.91 127 0.51 0.27 0.95 789 0.66 0.52 0.85 19 0.72 0.15 3.50 480 0.70 0.51 0.95 30 0.52 0.14 1.91 261 0.66 0.43 1.03 37 0.29 0.06 1.43 Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative IHC 3+ FISH-positive 630 0.57 0.44 0.74 178 1.42 0.71 2.84 388 0.73 0.50 1.06 408 0.57 0.41 0.79 721 0.66 0.51 0.85 767 0.67 0.52 0.86 0 1 2 3 4 5 ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor 45 Swain et al. SABCS 2012 Poster P5-18-26.

EMILIA Progression-Free Survival Subgroup Analyses Baseline characteristic All pts Total n 991 Cap + Lap Median, mos 6.4 T-DM1 Median, mos HR (95% CI) 9.6 0.66 (0.56, 0.78) Hormone Receptor Status T-DM1 better Cap + Lap better Age <65 yrs 65 yrs 853 138 6.0 8.1 9.8 7.0 0.62 (0.52, 0.74) 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR 545 426 7.1 5.6 9.0 10.3 0.72 (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third 118 361 512 5.7 6.8 6.5 10.8 9.6 9.0 0.51 (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) Data cut-off Jan 14, 2012 HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy. Hazard ratio 0.2 0.5 1 2 5 Verma et al. N Eng J Med 2012 (incl. supplementary appendix) Blackwell et al. ASCO 2012; Abst #LBA1

EMILIA Overall Survival Subgroup Analyses Cap + Lap T-DM1 Baseline Total Median Median HR characteristic n (mos) (mos) (95% CI) All patients 991 25.1 30.9 0.70 (0.56, 0.87) Age group <65 years 853 24.6 30.9 0.66 (0.52, 0.83) 65 74 years 113 27.1 NR 0.74 (0.37, 1.47) 75 years 25 NR 11.1 3.45 (0.94, 12.65) ER and PR status ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85) ER and PR 426 23.7 27.1 0.75 (0.54, 1.03) Line of therapy a First-line 118 27.9 NR 0.61 (0.32, 1.16) Second-line 361 NR 27.1 0.88 (0.61, 1.27) Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84) Hormone Receptor Status T-DM1 Better Cap + Lap Better Hazard ratio 0.2 0.5 1 2 5 From confirmatory OS analysis; data cut-off July 31, 2012.

HER2 ER Cross-talk Presented By Karen Gelmon at 2017 ASCO Annual Meeting

Single Agent HER2 targeted therapy adds modestly to endocrine therapy Presented By Karen Gelmon at 2017 ASCO Annual Meeting

ALTERNATIVE: Study Design Gradishar Abstract 1004 Presented By Karen Gelmon at 2017 ASCO Annual Meeting

ALTERNATIVE: Baseline Characteristics Presented By Karen Gelmon at 2017 ASCO Annual Meeting

ALTERNATIVE: Secondary Endpoint<br />PFS in all treatment arms Presented By Karen Gelmon at 2017 ASCO Annual Meeting

ALTERNATIVE: Secondary Endpoint<br />OS in all treatment arms Presented By Karen Gelmon at 2017 ASCO Annual Meeting

PERTAIN Study Design (Phase II) Presented By Karen Gelmon at 2017 ASCO Annual Meeting

Primary PFS Analysis (Stratified, ITT Population) Presented By Karen Gelmon at 2017 ASCO Annual Meeting

Summary HT and HER2 directed therapy Presented By Karen Gelmon at 2017 ASCO Annual Meeting

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

ASCO Clinical Practice Guidelines First Line Clinicians should recommend the combination of Trastuzumab, Pertuzumab and a Taxane for first line treatment, unless the patient has a oontraindication to Taxanes Type: Evidence quality: Strength of Recommendation: Evidence Based High Strong If a patient finished trastuzumab-based adjuvant treatment < 12 months before recurrence, clinicians should follow the second line Her 2 targeted therapy based treatment recommendations. Type: Evidence quality: Strength of Recommendation: Evidence Based Intermediate Moderate Giordano et al. J Clin Oncol 2014;32:2078

ASCO Clinical Practice Guidelines Second Line and Beyond If a patient s Her 2 positive advanced breast cancer has progressed during or after first-line Her 2 targeted therapy, clinicians should recommend trastuzumab emtansine (T-DM1) as second line treatment. Type: Evidence quality: Strength of Recommendation: Evidence Based High Strong If a patient s Her 2 positive advanced breast cancer has progressed during or after second line or greater Her 2 targeted therapy, but she has not received T-DM1, clinicians should offer T-DM1. Type: Evidence quality: Strength of Recommendation: Evidence Based High Strong Giordano et al. J Clin Oncol 2014;32:2078

ASCO Clinical Practice Guidelines Second Line and Beyond If a patient s Her 2 positive advanced breast cancer has progressed during or after second line or greater Her 2 targeted therapy, but she has not received Pertuzumab, clinicians may offer pertuzumab. Type: Evidence quality: Strength of Recommendation: Informal Consensus Insufficient Weak If a patient s Her 2 positive advanced breast cancer has progressed during or after second line or greater Her 2 targeted therapy, but she has already received pertuzumab and T-DM1, clinicians should recommend third-line or greater Her 2 targeted therapy-based treatment There is insufficient evidence to recommend one regimen over another Type: Evidence quality: Strength of Recommendation: Informal Consensus Insufficient Weak Giordano et al. J Clin Oncol 2014;32:2078

Real World Evidence European Data on outcomes of MBC patients ASCO 2017

Real World Evidence European Data on outcomes of MBC patients Delaloge et al, ASCO 2017

SEER Database: Her 2 Positive MBC Outcomes ASCO 2017

HER2 Positive De NOVO Stage IV disease <br />3-yr OS by stage and subtype Presented By Karen Gelmon at 2017 ASCO Annual Meeting

Clinical Pathway HER2+ MBC: 2015

Her 2 MBC 2017 Update DFI < 12 months T-DM1 (1 st line?)? Role of Pz post Role of Triplet Tx -Tras+Lap+AI - Tras + Pert + AI

Conclusion There is clear evidence that integration of Her 2 targeted therapy leads to significant clinical benefit Improved benefit with time with now real world evidence that confirms benefit We need to continue to investigate specific biomarkers to enhance the value of these therapies Our ability to sequence therapy should be based on improved understanding of treatment resistance and tumor biology along with patient consideration

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