Target biologico e meccanismo d azione dei farmaci anti-her2: il continuum dal setting Neoadiuvante alla malattia metastatica

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1 Target biologico e meccanismo d azione dei farmaci anti-her2: il continuum dal setting Neoadiuvante alla malattia metastatica Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Experimental Therapeutics

2 Outline Neoadjuvant therapy in HER2 positive disease Picking optimal treatment for adjuvant therapy of HER2 positive EBC State of the art in the management of HER2 positive advanced breast cancer Future trials in HER2 positive ABC

3 Neoadjuvant therapy in HER2+ EBC LESSONS LEARNED FROM NEOADJUVANT TRIALS I. First generation Trastuzumab + chemo > chemo alone

4 Trastuzumab and chemotherapy Trastuzumab + chemotherapy Chemotherapy alone MD Anderson 1 H+(T FEC) T FEC n=45 n= P=NR NOAH 2 H+(AT T CMF) AT T CMF n=117 n= P< pcr (%) No evidence of residual invasive cancer, both in breast and axilla No evidence of residual disease in breast tissue pcr, pathological complete response; H, trastuzumab; T, taxane FEC, 5-fluorouracil+epirubicin+cyclophosphamide; AT, doxorubicin+paclitaxel CMF, cyclophosphamide+methotrexate+5-fluorouracil; EC, epirubicin+cyclophosphamide 1. Buzdar AU, et al. 2007,2. Gianni L, et al. 2010

5 Improved pcr rate translates into improved outcome with Trastuzumab 5-year event-free survival 5-year overall survival *EFS, Event free survival; HR, Hazard ratio; OS, Overall survival. Gianni L, et al. 2014

6 FDA statement on pcr The absence of any residual invasive cancer on H&E evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypt0 ypn0 in the current AJCC staging system). This definition resumes the current understanding of major features of the intrinsic biology of early-stage breast cancer

7 Association of pcr and outcome by BC subtype: a FDA led meta-analysis (N=11,955) Cortazar et al, Lancet 2014

8 Dual HER2 blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS II. Second generation Dual HER2 blockade + chemo > single HER2 blockade + chemo

9 Rationale for Dual HER2 Targeting Based on Preclinical Data Trastuzumab Pertuzumab Lapatinib Anti-HER2 Antibodies Agent Antibody: binds to extracellular subdomain IV of HER2 Antibody: binds to extracellular subdomain II of HER2 Small molecule inhibitor: dual TKI of EGFR and HER2 Trastuzumab Pertuzumab MOA Blocks HER2 cleavage Induces ADCC Inhibits ligandindependent, HER2- mediated signaling Prevents dimerization with other ligandactivated HER receptors Stimulates ADCC Blocks ligand-induced heterodimer signaling Prevents signaling via truncated version of the HER2 receptor Leads to accumulation of HER2 at the cell surface to enhance H-ADCC P Signaling No Signaling Tyrosine Kinase Inhibitors Complementary MOA of H with either P or L provides a more comprehensive blockade of HER2 signaling P P X X Lapatinib Neratinib Resulted in greater antitumor activity than single agents in HER2-positive tumor models Signaling No Signaling Scheuer W, et al. Cancer Res. 2009;69: Scaltriti M, et al. Oncogene. 2009;28: Zhou Z, et al. In: Oncogene and cancer: from bench to clinic. InTech; Chapter 3.

10 pcr, % 95% CI pcr, % 95% CI Pertuzumab and trastuzumab 50 TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) Study dosing: q3w x 4 Gianni L, et al. Lancet Oncol 2011 DOI: /S (11) S U R G E R Y T H TH P H P 24 TP ER or PR positive ER and PR negative TH THP HP TP 6

11 Overview of dual blockade

12 Dual blockade better 74% 65% 48% 45% 38% 25% 20% 15% Increase in pcr Long CHT + duale anti- HER2 therapy Long CHT +Trastuzumab similar to short CHT+duale anti- HER2 Short CHT +Trastuzumab CHT allone

13 pcr by Arm and Intrinsic Subtype % N=11 N=52 N=51 N=35 N=123 N=173 Carey L et al. J Clin Oncol 35 s, # 500

14 PIK3CA mut status and pcr pcr GBG studies ypt0/ypn0 NeoAltto ypt0/is P= CHERLOB ypt0/is, ypn0 P=0.007 P=0.06 N=173 N=91 N=240 N=112 N=124 N=119 N=~35 N=~35 N=~35 N=108 Loibl S et al. J Clin Oncol 2014; Majewski J Clin Oncol 2015; Guarneri V et al. ESMO 2014

15 Beyond dual blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS III. Third generation Identify the subset which can benefit from a chemo-sparing regimen

16 HER2+ /HR- disease % PCR rates % Dual HER2 blockade alone 62% Dual HER2 blockade + taxane 73-80% Dual HER2 blockade + taxane + other agent (anthrac., carbo) Who are these patients with HER2+ HR- disease who perhaps do not need chemo? Based on NeoSphere, NeoAltto, Tryphaena

17 HER2+ /HR- disease PIK3CA mutations/ PTEN loss Improved tailoring? TIL s Immune signatures

18 Chemofree Therapy in HER2+ patients Neosphere THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TBCRC 0023 Stage II/III HER2+ bc 12 weeks of HL +/-ET 24 weeks of HL +/-ET S U R G E R Y TBCR006 Gianni L, et al. Lancet Oncol 2012; Rimawi M et al. J Clin Oncol 2013; Rimawi M, et al. SABCS THP HP HL+ET 12 HL+ET Overall ER+ ER

19 Trastuzumab Emtansine ± ET vs Trastuzumab + ET in HER2+/HR+ International, prospective, randomized phase II trial Wk 12 Pts with ER+ and/or PgR+, HER2+, ct1c - ct4a-c, cn, cm0 BC and adequate organ function, LVEF 50%, normal ECG (N = 375) T-DM1 3.6 mg/kg Q3W (n = 119) T-DM1 3.6 mg/kg Q3W + ET* (n = 127) Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET* (n = 129) Surgery *Tamoxifen if premenopausal; aromatase inhibitor (of investigator s choice) if postmenopausal. Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pcr). Primary endpoint: pcr (no invasive carcinoma in breast/nodes) Secondary endpoints: dynamic testing evaluation, EFS, OS, safety 1. Harbeck N, et al. SABCS Abstract S Hofmann D, et al. Trials. 2013;14:261.

20 ADAPT Trial Characteristic T-DM1 (n = 119) T-DM1 + ET (n = 127) Trastuzumab + ET (n = 129) Median age, yrs (range) 50.0 (21-78) 51.0 (27-76) 51.5 (23-77) ct, % 1 2 cn, % 0 1 PgR, % Negative Positive ER, % Negative Positive Central grading 3, % Median Ki67 (range) 40 (10-90) 40 (15-80) 35 (10-85)

21 ADAPT Trial Outcome, n/n (%) T-DM1 T-DM1 + ET pcr (ypt0 or ypt0/is, ypn0) All pts* Premenopausal women Postmenopausal women 48/117 (41.0) 22/58 (37.9) 26/59 (44.1) *P <.001 for comparison between each T-DM1 arm vs trastuzumab + ET. Low cellularity (< 500 tumor cells) or Ki67 decline 30%in 3-wk biopsy. Harbeck N, et al. SABCS Abstract S /123 (41.5) 24/63 (38.1) 27/60 (45.0) Trastuzumab + ET 18/119 (15.1) 8/59 (13.6) 10/60 (16.7) Near pcr (ypt1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2) Early response Nonresponders Responders 9/36 (25.0) 24/61 (39.3) 6/25 (24.0) 36/76 (47.4) 5/40 (12.5) 11/62 (17.7)

22 ADAPT Trial 12-wk T-DM1 increased pcr rate vs trastuzumab + ET in women with HER2+/HR+ EBC 41% vs 15%, respectively (P <.001) Addition of ET to T-DM1 did not raise pcr rate Menopausal status had minimal bearing on results Tolerable safety profile with low toxicity Early response significantly associated with increased pcr rate Detectable after 3 wks Authors conclude further investigation of T-DM1 in pts with EBC warranted Harbeck N, et al. SABCS Abstract S5-03.

23 Adjuvant therapy in HER2 positive EBC Optimal Adjuvant Therapy in 2016 for the average patient with HER2-positive breast cancer

24 The Adjuvant Setting: Present Situation Trastuzumab given concurrently with Taxanes after Anthracycline-based chemotherapy is the most common practice in Europe N = 465 medical oncologists answering a questionnaire Trastuzumab with Tax, after A-CTH Trastuzumab seq, after A-CTH TCH Trastuzumab not available Zardavas D et al - Ann Oncol Aug;25(8):

25 First generation trials HERA (ex-usa) BCIRG 006 (global) IHC / FISH (n=5102) Observation 1 year 2 years FISH (n=3222) 1 year 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=3505) 1 year IHC / FISH (n=2030) 1 year 1 year Standard CTx Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Herceptin Paclitaxel IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation

26 Long-term DFS benefit with adjuvant Trastuzumab for 1 year Study HERA 1 4 CT+/-RT H vs. CT+/-RT BCIRG AC TH H vs. AC T TCH vs. AC T Combined analysis 6-8 (NCCTG N9831/ NSABP B-31) AC TH H vs. AC T HR, hazard ratio Follow-up (years) N Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011, 4. Goldhirsch A, et al Slamon D, et al. 2011; 6. Romond EH, et al. 2005; 7. Perez EA, et al. 2011; 8. Perez EA, et al HR Favours 1 Favours 2 Trastuzumab HR (95% CI) observation

27 Timing of Distant Recurrences in relation to Adjuvant Trastuzumab Romond EH, N Engl J Med 2005; 353: NSABP B-31 and NCCTG N9831

28 Escalation 1. Longer trastuzumab duration (Hera 2y arm) 2. Adding bevacizumab to trastuzumab (Beth) 3. Dual HER2 blockade - Lapatinib + trastuzumab (ALTTO) - Pertuzumab + trastuzumab (APHINITY) - Extended neratinib (EXTENET) 4. T-DM1 after neoadjuvant CT + trastuzumab in case of residual disease (Katherine)

29 HERA 2 years Goldhirsch A et al. The Lancet Volume 382, No. 9897, p , 21 September 2013

30 Slamon D et al, SABCS 2-13, abstract #S1-03 Adding bevacizumab Cohort 1 Non-Anthracycline TCH Node positive or high-risk node negative HER2+ H Cohort 2 Anthracycline N= 3231 N= 278 TH FEC H Arm 1A TCH H Arm 1B TCHBev HBev TH Arm 2A H FEC Arm 2B THBev HBev FEC

31 Slamon D et al, SABCS 2-13, abstract #S1-03 Adding bevacizumab IDFS OS No Bevacizumab 92% 96% + Bevacizumab 92% 97%

32 Adding lapatinib Anti-HER2 therapy: 4 groups assigned by randomization Trastuzumab Lapatinib T x 12 wks Trastuzumab and Lapatinib 6 weeks (T) x 52 weeks (L) x 52 weeks L x 34 weeks x 52 weeks x 52 weeks 3 modalities of adjuvant CT administration per physician s choice Design 1 Chemotherapy Anthracycline Taxane Anti-HER2 therapy 12 to 18 weeks 52 weeks * R Design 2a 9 to 12 weeks 12 weeks * R Design 2b Docetaxel + Carboplatin 18 weeks Anti-HER2 therapy 52 weeks Anti-HER2 therapy * R: refers to the timing of randomization * R 52 weeks

33 Adding lapatinib MFU = 4.5 yrs M. Piccart et al. JCO 2015

34 ExteNET HER2+ Stage II-IIIC node positive BC following CT + 12 months of trastuzumab (adj) (N=2821) R Neratinib 240 mg orally daily for 1 year Placebo Orally daily for 1 year DFS DFS CT, chemotherapy; adj, adjuvant; DFS, disease-free survival; BC, breast cancer. Press release - Puma Biotechnology July 22nd, 2014 Extended DFS by 33% compared with placebo (HR = 0.67; P =.0046)

35 ExteNET Endpoint Estimated event-free survival rate at 2 years, %* Neratinib Placebo (N=1420) (N=1420) Hazard ratio (95% CI) P Value Invasive disease-free survival (0 50, 0 91) Disease-free survival including (0 46, 0 84) ductal carcinoma in situ Distant disease-free survival (0 53, 1 04) Time to distant recurrence (0 50, 1 00) CNS recurrence Intention-to-treat population * Event-free rates for all endpoints, except for CNS recurrence for which cumulative incidence is reported. Stratified Cox proportional hazards model. Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray s method was used. CNS = central nervous system. Chan et al. Lancet Oncol 2016

36 Disease-free survival (%) ExteNET Intention-to-treat population % 95.6% 93.9% 91.6% 2.3% P-value = HR (95% CI) = 0.67 ( ) 50 Neratinib Placebo No. at risk Neratinib Placebo Months after randomization Chan et al. Lancet Oncol 2016

37 Disease-free survival (%) Disease-free survival (%) ExteNET Hormone receptor-positive Hormone receptor-negative % % % 95.4% 91.2% 4.2% % 95.0% 92.0% P = HR (95% CI) = 0.51 ( ) 60 P = 0.74 HR (95% CI) = 0.93 ( ) No. at risk Neratinib Placebo Months after randomization Neratinib Placebo No. at risk Neratinib Placebo Months after randomization Neratinib Placebo Chan et al. Lancet Oncol 2016

38 ExteNET Neratinib (n=1408) Placebo (n=1408) n (%) All grades Grade 3 4 All grades Grade 3 4 Diarrhea 1343 (95.4) 562 (39.9) 499 (35.4) 23 (1.6) Nausea 605 (43.0) 26 (1.8) 303 (21.5) 2 (0.1) Fatigue 382 (27.1) 23 (1.6) 283 (20.1) 6 (0.4) Vomiting 369 (26.2) 47 (3.3) 113 (8.0) 5 (0.4) Abdominal pain, general 340 (24.1) 24 (1.7) 144 (10.2) 3 (0.2) Headache 278 (19.7) 8 (0.6) 275 (19.5) 6 (0.4) Abdominal pain, upper 212 (15.1) 11 (0.8) 96 (6.8) 3 (0.2) Rash 211 (15.0) 5 (0.4) 100 (7.1) 0 Decreased appetite 170 (12.1) 3 (0.2) 40 (2.8) 0 Muscle spasms 159 (11.3) 1 (0.1) 45 (3.2) 1 (0.1) Dizziness 146 (10.4) 3 (0.2) 128 (9.1) 3 (0.2) Arthralgia 86 (6.1) 2 (0.1) 162 (11.5) 4 (0.3) Chan et al. Lancet Oncol 2016

39 APHINITY S U R G E R Y Central Confirmation of HER2 status N=4806 R A N D O M I Z A T I O N 52 weeks Trastuzumab Pertuzumab Trastuzumab Placebo

40 Katherine Neoadjuvant CT + trastuzumab Residual invasive cancer R T-DM1 Trastuzumab Primary endpoint : IDFS 900/1400 patients recruited as of today

41 KAITLIN HER2+ Node+ or Node-, ERand T>2cm R AC x 4 or FEC x3 AC x 4 or FEC x3 TAXANE TRASTUZUMAB PERTUZUMAB T-DM1 PERTUZUMAB IDFS HO 89,5% 93,1% 2100/2500 women recruited Worrysome : taxane + trastuzumab = T-DM1 = T-DM1 + pertuzumab in the first line metastatic MARIANNE trial! 41

42 Escalation attempts : preliminary conclusions Failed Succeeded V V V Trastuzumab x 2y Trastuzumab + bevacizumab Trastuzumab + lapatinib Trastuzumab followed by neratinib? Trastuzumab + pertuzumab?? T-DM1 after neoadj CT + trast? V

43 Tolaney S, NEJM 2015 De-Escalation

44 Tolaney S, NEJM 2015 pt1-pt3 pn0 HER2+

45 De-Escalation attempts : preliminary conclusions Failed Succeeded V(so far ) Shorten trastuzumab duration Eliminate the anthracycline component? Use T-DM1 + pertuzumab instead of taxane + trastuzumab + pertuzumab V (in selected pts!)?

46 TILs in HER2 positive BC Patients assessed 489 pts from Arm A (chemo) 456 pts from Arm C (chemo with trastuzumab) Median follow-up of 6.9 yrs for RFS Disease characteristics and outcome similar to parent N9831 cohort 54% of tumors hormone receptor positive 14% node-negative disease

47 % RFS TILs in HER2 positive BC Arm A (chemo) Arm C (chemo + tras) LPBC N=48 non-lpbc N=441 LPBC N=46 non-lpbc N= Log Rank = Log Rank = LPBC= lymphocyte predominant breast cancer Years from Randomization

48 TILs in HER2 positive BC In LPBC patient group (str-tils 60%) Arm A: 10yr RFS = 90.9% Arm C: 10yr RFS = 80.0% HR = 2.43; 95%CI 0.58 to 10.22, p=0.22 In non-lpbc patient group (str-tils < 60%) Arm A: 10yr RFS = 64.3% Arm C: 10yr RFS = 79.6% HR = 0.49; 95%CI 0.35 to 0.60, p<0.0001

49 (Neo)Adjuvant therapy in HER2+ EBC 1. Adjuvant trastuzumab treatment for 1 year is the standard of care. 2. Longer or shorter durations of adjuvant trastuzumab treatment are not justified by currently available data. 3. Dual targeting in neoadjuvant setting increase pcr 4. Dual HER2 blockade with the incorporation of lapatinib will not be applied in clinical practice the strategy assessing the addition of pertuzumab is ongoing (2016?). 5. We still lack a validated biomarker beyond HER2 for improved treatment tailoring. We need to: 1. Identify patients with disease resistant to HER2 blockade. 2. Identify patients not needing intensified regimens. 3. Identify patients candidate for chemotherapy-free regimens.

50 Targeting HER2 in ABC

51 Targeting HER2: First line n=406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N=808) 1:1 Docetaxel 6 cycles recommended Pertuzumab + trastuzumab PD n=402 Docetaxel 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Baselga et al, NEJM 2012

52 Overall survival (%) Targeting HER2: First line n at risk PHT HT Time (months) % 89% 1 year years % 69% years % 50% PHT: 113 events; median not reached HT: 154 events; median 37.6 months HR % CI = 0.52, 0.84 p = Swain et al, N Engl J Med 2015;372, 724

53 Overall survival (%) Targeting HER2: First line n at risk PHT HT PHT: 168 events; median 56.5 months HT: 221 events; median 40.8 months Time (months) Δ 15.7 months HR % CI = 0.56, 0.84 p = Data cut-off: February 2014 CI, confidence interval; H, trastuzumab; HR, hazard ratio; P, pertuzumab; T, docetaxel Swain et al, N Engl J Med 2015;372, 724

54 Targeting HER2: First line Prior (neo)adjuvant chemotherapy Region Age group Race Disease type ER/PR status All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other Visceral disease Non-visceral disease Positive Negative Favours pertuzumab Favours placebo N HR 95% CI (0.55, 0.82) (0.48, 0.85) (0.53, 0.93) (0.47, 0.91) (0.37, 1.07) (0.30, 0.85) (0.57, 1.16) (0.56, 0.87) (0.31, 0.90) (0.55, 0.83) (0.26, 2.73) (0.49, 0.82) (0.11, 1.45) (0.58, 1.17) (0.13, 1.06) (0.48, 0.74) * (0.66, 1.85) (0.53, 0.96) (0.47, 0.81) HER2 status IHC 3+ FISH-positive (0.53, 0.81) (0.56, 0.85) Data cut-off: February ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; HR, hazard ratio; IHC, immunohistochemistry; PR, progesterone receptor * Based on a small number of patients, not expected from a mechanistic point of view and is considered likely to be a chance finding 2,

55 Targeting HER2: Second line T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

56 Targeting HER2: Second line HER2+ (central) LABC or MBC (N=980) Prior taxane and Herceptin Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 T-DM1 3.6 mg/kg q3w IV Xeloda 1000 mg/m 2 orally bid, days 1 14, q3w + lapatinib 1250 mg/day orally qd PD PD Stratification factors: World region, number 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 response, time to symptom progression and quality of life LABC, locally advanced breast cancer; MBC, metastatic breast cancer; tx, treatment; PD, progressive disease; q3w, every 3 weeks; bid, twice daily; qd, every day; PFS, progression free survival; OS, overall survival; ORR, objective response rate

57 Targeting HER2: Second line Primary analysis data Confirmatory OS analysis data lapatinib + Xeloda T-DM1 lapatinib + Xeloda T-DM1 Randomised, n Treated, n On treatment at data cutoff date Median follow-up, mo (range) First patient in: Last patient in: Primary Clinical data cut-off: Updated analysis data cut-off: 23 rd February th October th January st July 2012 Verma ESMO 2012, Oral Presentation LBA12

58 Proportion progression-free Targeting HER2: Second line Median (mos) No. events X + lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) p< Unstratified HR=0.66 (p<0.0001) No. at risk by independent review: X + lap T-DM Time (mos) Adapted from Verma et al, NEJM, 1 October Welslau et al, ESMO 2012 Poster 329P

59 Percent Proportion progression-free Targeting HER2: Second line 50 ORR Difference: 12.7% (95% CI, 6.0, 19.4) P<0/ % DOR Median, mos (95% CI) X + lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) % /389 X + lap 173/397 T-DM No. at risk X + lap T-DM Adapted from Verma et al, NEJM, 1 October Welslau et al, ESMO 2012 Poster 329P

60 Proportion surviving Targeting HER2: Second line % 85.2% Median (months) No. of events X + Lap T-DM Stratified HR=0.682 (95% CI, 0.55, 0.85); P= Efficacy stopping boundary P= or HR= % 51.8% No. at risk: X + Lap T-DM Time (months) Adapted from Verma et al, NEJM, 1 October Welslau et al, ESMO 2012 Poster 329P

61 Targeting HER2: Third line Stratified by world region, number of prior tx for MBC, presence of visceral disease Pts with HER2+ advanced breast cancer, 2 prior anti-her2 therapies* (N = 602) T-DM1 3.6 mg/kg q3w IV (n = 404) Therapy of Physician s Choice (n = 198) PD PD T-DM1 *Previous treatment with trastuzumab, lapatinib, and a taxane required for eligibility. Optional crossover. Primary endpoints: PFS by investigator, OS Secondary endpoints: ORR by investigator, safety Wildiers H, et al. SABCS Abstract S5-05.

62 Targeting HER2: Third line Characteristic Age, yrs, % Younger than 65 yrs yrs ECOG PS, % *Excluding hormonal therapies. TPC (n = 198) T-DM1 (n = 404) ER+ and/or PgR+, % Visceral involvement, % Metastatic disease, % Brain metastasis, % Median no. of prior BC therapies,* n (range) 3, % 4-5, % > 5, % Wildiers H, et al. SABCS Abstract S (1-19) (1-14)

63 Targeting HER2: Third line Wildiers H, et al. SABCS Abstract S5-05.

64 Targeting HER2: Third line Median OS, Mos TPC (n = 198) T-DM1 (n = 404) Stratified HR (95% CI) P Value All pts ( )*.0007 Sensitivity analysis (pts censored at crossover to T-DM1) ( ).0002 Wildiers H, et al. SABCS Abstract S5-05.

65 Targeting HER2 in ABC CLEOPATRA Vs Doce+Trast Emilia Vs Lap-Cap TH3RESA Vs TPS

66 Targeting HER2 and mtor N = 719 Locally advanced or metastatic HER2+ breast cancer No prior therapy for advanced or metastatic disease (except endocrine therapy) Prior (neo)adjuvant TRAS and/or chemotherapy allowed 1 Measurable disease or presence of bone lesions (lytic or mixed) Endpoints Randomized 2:1 Stratification factors: Prior neo/adjuvant TRAS Visceral metastases Everolimus (10 mg PO daily) + Paclitaxel 2 + Trastuzumab 3 Placebo + Paclitaxel 2 + Trastuzumab 3 Therapy until disease progression or intolerable toxicity 4 Primary: PFS (investigator-assessed) Overall population and HR subpopulation Secondary: OS, ORR, CBR, Time to response, Safety, Duration of response 1 Discontinued > 12 mo before randomization; 2 Paclitaxel: 80 mg/m 2 weekly; 3 Trastuzumab: 4 mg/kg loading dose on day 1 at cycle 1 followed by 2 mg/kg weekly doses 4 Patients could discontinue any study treatment due to AEs; other study treatments continued until disease progression or intolerable toxicity Hurvitz 2014, SABCS

67 Probability, % Targeting HER2 and mtor Hazard ratio = 0.78; 95% CI [0.65, 0.95] Log-rank P value =.0067 Median PFS Everolimus: 7.00 months; 95% CI [6.74, 8.18] Placebo: 5.78 months; 95% CI [5.49, 6.90] Censoring times Everolimus (n/n = 196/284) Placebo (n/n = 219/285) 0 Number of Patients Still at Risk Everolimus Placebo Abbreviations: CI, confidence interval Time, weeks

68 Targeting HER2 HER2-positive (central) LABC a or MBC No prior chemotherapy for LABC/MBC >6 months from prior neo-/adjuvant vinca alkaloid or taxane chemotherapy N = 1095 Trastuzumab + docetaxel (8 mg/kg LD then 6 mg/kg or 75 mg/m 2 q3w) OR Trastuzumab + paclitaxel (4 mg/kg LD then 2 mg/kg + 80 mg/m 2 qw) T-DM1 + placebo b (3.6 mg/kg mg LD then 420 mg q3w) T-DM1 + pertuzumab (3.6 mg/kg mg LD then 420 mg q3w) Stratification factors: World region, Prior neo-/adjuvant therapy (if Yes: prior trastuzumab/lapatinib), Visceral disease Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority assessed Key secondary end points: OS, PFS by investigator, ORR, Safety, Patient-reported outcomes LD, Loading dose. a Locally progressive or recurrent and not amenable to resection with curative intent; b Pertuzumab placebo.

69 Targeting HER2 HT T-DM1 T-DM1+P Randomized, n Treated (safety population) a, n 353 b Median duration of follow-up, mo. (range) 35 (0.1 48) 35 (0.1 50) 35 (0.1 48) First patient in: July 6, 2010 Last patient in: May 2, 2012 Clinical data cutoff: September 16, 2014

70 Progression-Free Survival (%) Targeting HER2 HT T-DM1 T-DM1+P 100 Median PFS (mo.) Events (no.) Stratified HR (97.5% CI) vs HT 0.91 ( ) P= ( ) P= Stratified HR (97.5% CI) vs T-DM ( ) No. at Risk 20 0 HT T-DM1 T-DM1+P Time (mo.) HT T-DM1 T-DM1+P

71 Patients, % Patients without progression, % Targeting HER Objective Response Rate 67.9% 64.2% 59.7% Duration of Response Median, mo. (95% CI) HT T-DM1 T-DM1+P 12.5 ( ) 20.7 ( ) 21.2 ( ) / / /299 HT T-DM1 T-DM1+P No. at Risk HT T-DM1 T-DM1+P 20 0 HT T-DM1 T-DM1+P Time (mo.) Error bars depict 95% confidence intervals.

72 Targeting HER2 Chemo Trastuzumab Pertuzumab PHEREXA, II line PERUSE, I line NCT , I line NCT , I or II line NCT , II line Trastuzumab Pertuzumab Endocrine Th. PERTAIN, I line (HR+) T-DM1 MARIANNE, I line Pertuzumab Chemo Trastuzumab NCT , I line Trastuzumab Lapatinib No resp or PD HERLAP, I line Chemo Trastuzumab Lapatinib Lapatinib Chemo Pertuzumab T-DM1 NCT , II line NCT , I, II line Trastuzumab Pertuzumab PD T-DM1 NCT , I line Chemo Bolero 1, I line Trastuzumab Everolimus

73 Trastuzumab shows synergy with Anti-PD1 Blockade PD1 Inhibitory T-Cell Receptor, engaged by PD-L1/2 (tumor microenvironment) Trastuzumab and anti-pd1 mab Synergy Ribas A. N Engl J Med 2012;26(366): Stagg J. et al. PNAS 2011

74 Next future

75 Next future

76 Next future

77 FIH phase 1 Study with Margetuximab (Burris HA) To evaluate the safety of margetuximab using two dosing regimens V H Fab C H1 VL C L C H2 Fc C H3 Tumor Cell A D C C A D C C A D C C

78 FIH phase 1 Study with Margetuximab (Burris HA) All evaluable pts Evaluable MBC 39/60 prior antiher2 therapy 22/23 prior antiher2 therapy

79 Therapy in HER2+ ABC 1. Dual blockade in first line standard of care 2. T-DM1 in second line better than lapatinib and capecitabine 3. Defining the right sequence of TDM1 following dual blockade 4. Exploring the role of immune system in explaining response to anti HER2 agents

80 Thank you