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Targeting HER family receptors in breast cancer Prof. Sabino De Placido Dip. di Endocrinologia ed Oncologia Molecolare e Clinica Università Federico II.

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Presentation on theme: "Targeting HER family receptors in breast cancer Prof. Sabino De Placido Dip. di Endocrinologia ed Oncologia Molecolare e Clinica Università Federico II."— Presentation transcript:

1 Targeting HER family receptors in breast cancer Prof. Sabino De Placido Dip. di Endocrinologia ed Oncologia Molecolare e Clinica Università Federico II --- Napoli, Italia

2 Targeting HER2: Key points HER2 gene amplification and/or overexpression occurs in about 20% of breast cancers and is associated with more-aggressive disease and, until the advent of HER2-targeted agents, a worse outcome The monoclonal antibody, trastuzumab (which targets HER2), and the small molecule tyrosine kinase inhibitor, lapatinib (which targets HER1 and HER2), have considerable efficacy in HER2-positive breast cancer

3 Adjuvant Setting What we know Trastuzumab has changed the natural history of early HER2+ BC Year

4 Incidence of MBC without Herceptin Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countries Weisgerber-Kriegl et al, ASCO 2008 Patients, n 27,737 20,000 18,000 16,000 14,000 12,000 10, Herceptin introduced No. of patients prevented from developing metastases Year

5 More than patients were recruited in 4 international clinical trials Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006 NCCTG N9831 (USA) HERA (ex-USA)BCIRG 006 (global) NSABP B-31 (USA) IHC / FISH (n=5,090) Observation 1 year 2 years IHC / FISH (n=3,505) 1 year FISH (n=3,222) 1 year IHC / FISH (n=2,030) 1 year Docetaxel Docetaxel + carboplatin Doxorubicin + cyclophosphamide Trastuzumab Standard CTx Paclitaxel IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy

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7 Neoadjuvant setting What we know

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9 Adjuvant setting What we do not know Small, node negative tumors are under represented in clinical trials

10 Overall 7,164 pts. with pT1pN0 tumors –median follow-up yrs.) –600 pts. with HER-2 + tumors % HER-2 + disease –ranging between 7 and 10% Absolute risks of distant relapse HER2+ –5 yrs. ± 10-15% –10 yrs % Increased risk of disease relapse if HER-2 + –hazard ratios ranging between 2.4 and 8.99 Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Results Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

11 Caveats - heterogeneity in adjuvant therapies - HRs status not always centrally revised - in 3 out of 7 studies pT1c tumors were eligible - only 2 out of 7 studies evaluate outcome by combination of HER-2 and HRs status “Take-home” messages - there is a substantial degree of concordance in considering HER-2 + patients with pT1pN0 tumors at increased risk of relapse compared to the HER-2 negative population (2 to 9 fold increase) Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Caveats and Conclusions Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010

12 Key question Is proportional benefit from adjuvant systemic therapies dependent on disease stage ?

13 Potential options for adjuvant treatment of endocrine-resistant pT1b pN0 tumors Docetaxel-Cyclophosphamide (TC) x 4 + Trastuzumab* (lack of phase III data) Docetaxel-Carboplatin-Trastuzumab (TCH) x 6 (BCIRG 006 data) HER-2 + * concomitant trastuzumab > sequential trastuzumab Trastuzumab

14 Treatment decision: a multi-factorial process Patient : Co-morbidities Age Patient : Expectations Preferences Tumor* : Size Vascular invasion Ki-67 Treatment decision

15 Adjuvant setting What we do not know Duration of Trastuzumab

16 Adjuvant trials with different duration of trastuzumab administration HERA (PI M. Piccart): sample size ~ –12 vs 24 months of H following adjuvant CT Phare (PI X. Pivot): sample size ~ –6 vs 12 months of H following adjuvant CT Persephone (UK-NCRI): sample size ~ –6 vs 12 months of H following adjuvant CT Hellenic Oncology Group (Greece): sample size –6 vs 12 months of H with ddDoc after FEC SOLD (PI H. Joensuu): sample size ~ –HD 3-wkly x3 ->FE 75 C x3 vs –HD 3-wkly x3 ->FE 75 C x3 -> H 3-wkly x14 ShortHER (PI PF. Conte): sample size ~ –D 3-wkly x3 + H weekly x 9 -> FE 60 C x3 vs –AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14 HERA (PI M. Piccart): sample size ~ –12 vs 24 months of H following adjuvant CT Phare (PI X. Pivot): sample size ~ –6 vs 12 months of H following adjuvant CT Persephone (UK-NCRI): sample size ~ –6 vs 12 months of H following adjuvant CT Hellenic Oncology Group (Greece): sample size –6 vs 12 months of H with ddDoc after FEC SOLD (PI H. Joensuu): sample size ~ –HD 3-wkly x3 ->FE 75 C x3 vs –HD 3-wkly x3 ->FE 75 C x3 -> H 3-wkly x14 ShortHER (PI PF. Conte): sample size ~ –D 3-wkly x3 + H weekly x 9 -> FE 60 C x3 vs –AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14

17 Metastatic Disease

18 Overall Survival by Trastuzumab Treatment Groups Overall Survival Probability Months from Diagnosi Negative No Trastuzumab Trastuzumab HER2+ / Herceptin HER2+ / No Herceptin HER2-

19 What we Know The first line

20 HERNATA Study

21 HERNATA study : results Time to Progression Overall Survival Andersson JCO 2010

22 Time to Treatment Failure HERNATA study: results Andersson JCO 2010

23 HERNATA study : safety profile Andersson JCO 2010

24 The second line What we Know

25 Tyverb plus capecitabine: significantly longer TTP in difficult to treat population (EGF100151, independent assessment) Cumulative progression-free (%) Tyverb + capecitabine Capecitabine HR: 0.57 (95% CI: 0.43, 0.77) p= wks (4.3 mos) 27.1 wks (6.2 mos) 1. Cameron et al. Breast Cancer Res Treat 2008;[Epub ahead of print]. Figure Adapted from Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat, 2008 Epub ahead of print, with kind permission of Springer Science and Business Media.

26 Beyond the second line What we Know

27 Lapatinib in combination with trastuzumab significantly prolonged PFS compared with lapatinib alone (EGF104900) Lapatinib Lapatinib + trastuzumab n=145n=146 Progressed or died, n Median, wks HR (95% CI)0.73 (0.57, 0.93) p value0.008 Subjects at risk: 148 Lapatinib Lapatinib + trastuzumab month PFS Cumulative progression-free (%) 13% 28% Time from randomisation (weeks)

28 Updated overall survival in ITT (EGF104900) L n=145 L+T n=146 Died, n (%)113 (78)105 (72) Median, months9.514 Hazard ratio (95% CI)0.74 (0.57, 0.97) Log-rank p value month OS 80% 70% 12 month OS 56% 41% Cumulative % alive without progression Patients at risk 148 L L+T Time from randomization (months) L+T L

29 Lapatinib effect on ErbB2 accumulation at cell membrane: novel mechanism for enhanced effects of combined anti-ErbB2 therapy Lapatinib has been shown to enhance antitumour effect of trastuzumab in vitro and in clinical studies This study explored the mechanism for this effect by investigating impact of lapatinib and trastuzumab on receptor expression and signalling Treatment: lapatinib, trastuzumab, or both ErbB2-positive BC cells (SKBR3 and MCF7-HER2) In vitro assays: Receptor expression, phosphorylation, signalling, tumour growth Mouse xenograft Scaltriti et al., J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 3594 and poster Scaltriti et al., Oncogene 2009;

30 HER2+ and HR+ What we Know

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32 HER2 and hormone receptor-positive BC Clinical trials to assess therapy Cortes Nat Rev Clin Oncol 2010

33 HER2 and hormone receptor-positive BC Clinical trials to assess therapy Cortes Nat Rev Clin Oncol Overall response rates (%) TAnDEM EGF30008 Combination with Aromatase inhibitors Combination with chemotherapy H0648gM77001 Trastuzumab + anastrozole Lapatinib + letrozole Trastuzumab + paclitaxel Trastuzumab + docetaxel Drug regimen Figure 1: Overall response rates in HER2-positive and hormone receptor-positive metastatic breast cancer. Anti-HER2 therapy was combined either with chemotherapy or aromatase inhibitors in four pivotal trials. The combination with chemotherapy showed higher overall response rates

34 The Future What else we Know Trastuzumab + Pertuzumab

35 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Pertuzumab and trastuzumab have complementary mechanisms of action ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain HER2 Dimerization domain Pertuzumab HER1/3/4 Trastuzumab Subdomain IV Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC

36 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, MBC, metastatic breast cancer; PD, progressive disease Patients with HER2-positive MBC centrally confirmed (N = 808) Placebo + trastuzumab n=406 Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: − Pertuzumab/Placebo:840 mg loading dose, 420 mg maintenance − Trastuzumab:8 mg/kg loading dose, 6 mg/kg maintenance − Docetaxel:75 mg/m 2, escalating to 100 mg/m 2 if tolerated 1:1 n=402 Docetaxel* ≥6 cycles recommended PD Pertuzumab + trastuzumab Docetaxel* ≥6 cycles recommended PD * 6 cycles allowed at investigator discretion CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line setting

37 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Primary endpoint: Independently assessed PFS n = 433 PFS events D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab n at risk Ptz + T + D Pla + T + D Time (months) Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months HR = % CI 0.51 ‒ 0.75 p< ∆ = 6.1 months Progression-free survival (%) Stratified by prior treatment status and region

38 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab n at risk Pertuzumab + T + D Placebo + T + D Time (months) Ptz + T + D: 69 events Pla + T + D: 96 events HR = 0.64* 95% CI 0.47 ‒ 0.88 p = * * The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012) Overall survival (%)

39 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Cardiac tolerability LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Investigator-assessed symptomatic LVSD* 1.8%1.0% Independently adjudicated symptomatic LVSD* 1.0% Fall in LVEF to <50% and by ≥10 percentage points from baseline 6.6%3.8% * LVSD was defined as NYHA class III/IV

40 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Adverse events (all grades) ≥25% incidence or ≥5% difference between arms Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea184 (46.3)272 (66.8) Alopecia240 (60.5)248 (60.9) Neutropenia197 (49.6)215 (52.8) Nausea165 (41.6)172 (42.3) Fatigue146 (36.8)153 (37.6) Rash96 (24.2)137 (33.7) Decreased appetite105 (26.4)119 (29.2) Mucosal inflammation79 (19.9)113 (27.8) Asthenia120 (30.2)106 (26.0) Peripheral edema119 (30.0)94 (23.1) Constipation99 (24.9)61 (15.0) Febrile neutropenia30 (7.6)56 (13.8) Dry skin17 (4.3)43 (10.6)

41 Copyrights for this presentation are held by the author/presenter. Contact them at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6-10, Summary and conclusions CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC –Median PFS increased by 6.1 months from 12.4 to 18.5 months –The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature) The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin –These adverse events were primarily grades 1 ‒ 2, manageable, and occurred during docetaxel therapy –There was no increase in cardiac adverse events or LVSD This new regimen may be practice-changing in HER2-positive first-line MBC

42 The Future What else we Know T-DM1

43 43 Monoclonal antibody: trastuzumab Target expression: HER2 Highly potent chemotherapy (maytansine derivative) Cytotoxic agent: DM1 Systemically stable Breaks down in target cancer cell Linker T-DM1 Trastuzumab emtansine (T-DM1): the first- in-class HER2-targeted antibody-drug conjugate

44 44 Randomized, phase II, international, open-label study b Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary end points: PFS by investigator assessment, and safety Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover Key secondary end points: OS, ORR, DOR, CBR, and QOL Study Design TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC 1:1 HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m 2 q3w (n=70) Crossover to T-DM1 (optional) PD a T-DM1 3.6 mg/kg q3w IV (n=67) PD a a Patients were treated until PD or unacceptable toxicity. b This was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.

45 45 Time (months) Progression-Free Survival by Investigator Randomized Patients Proportion progression-free Number of patients at risk T+D T-DM Hazard ratio and log-rank P value were from stratified analysis. Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Median PFS, mos Hazard ratio95% CI Log-rank P value –

46 46 Duration of objective response (months) Duration of Response by Investigator Patients with Measurable Disease at Baseline with an Objective Response Proportion progression-free Number of patients at risk T+D T-DM Kaplan-Meier estimates are shown. a NR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm Median DOR, mos95% CI 9.5 NR a 6.6–10.6 – Trastuzumab + docetaxel (n=40) T-DM1 (n=43)

47 47 Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% ( Grade ≥3) of Patients a Green represents those AEs with ≥20% difference between treatment arms. a In either treatment arm. b No adverse events listed were grade 5. c Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. d Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. e National Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade ≥3 for this AE. AE All grade, n (%)Grade ≥3 b, n (%) Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Alopecia44 (66.7)3 (4.3) ee Fatigue30 (45.5)34 (49.3)3 (4.5)3 (4.3) Nausea29 (43.9)33 (47.8)02 (2.9) Diarrhea30 (45.5)11 (15.9)2 (3.0)0 Peripheral edema29 (43.9)7 (10.1)3 (4.5)0 Increased AST4 (6.1)27 (39.1)06 (8.7) Pyrexia15 (22.7)27 (39.1)1 (1.5)0 Headache12 (18.2)25 (36.2)00 Back pain20 (30.3)18 (26.1)3 (4.5)1 (1.4) Increased ALT4 (6.1)16 (23.2)06 (8.7) Pneumonia1 (1.5)6 (8.7)04 (5.8)

48 48 Cardiac Safety Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively Asymptomatic LV dysfunction There were no clinically significant cardiac events reported LVEF assessment Trastuzumab + docetaxel T-DM1 Local assessment Patients assessed6567 Patients with post-baseline LVEF ≤40%2a2a 0 Central assessment Patients assessed6065 Patients with post-baseline LVEF ≤40%1b1b 0 a Both patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting. b This patient did not receive prior treatment with an anthracycline.

49 49 Summary and Conclusions This is the first randomized study to evaluate an antibody-drug conjugate for HER2- positive MBC First-line treatment of HER2-positive MBC with T-DM1, compared with trastuzumab + docetaxel was associated with: –A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P value=0.0353) –Similar ORR but more durable responses (64.2%, median duration not reached vs. 58.0%, median duration 9.5 months) –A lower rate of grade ≥3 AEs (46.4% vs 89.4%) These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index –Improved PFS with T-DM1 may result from improved tolerability/duration of treatment/response and intrinsic potency of HER2-targeted DM1 T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC

50 HER2-positive LABC or MBC (N=980) Previously received trastuzumab-based therapy Lapatinib (1250 mg/day, days 1–21) + capecitabine (1000 mg/m 2, days 1–14) q3w T-DM1 (3.6 mg/kg) q3w TDM4370g (EMILIA) Phase III Study: T-DM1 vs Capecitabine + Lapatinib in HER2-Positive MBC Multicenter, randomized, open-label study Treatment continues until progressive disease/unacceptable toxicity Primary end points: PFS by IRF, OS, 1-y and 2-y survival rates, Safety Secondary end points: PFS by INV, ORR, CBR, DoR, QOL, TTF NCT :1

51 51 HER2-positive progressive or recurrent locally advanced BC or previously untreated MBC (n=1092) Trastuzumab + taxane (n=364) T-DM1 + pertuzumab (n=364) T-DM1 + placebo (n=364) BC = breast cancer; MBC = metastatic breast cancer; PFS = progression-free survival MARIANNE: Primary efficacy objective: –PFS assessed by an independent review facility Primary safety objective: –To compare the safety of T-DM1 + pertuzumab or T-DM1 + placebo vs trastuzumab + taxane

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