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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 --- Napoli, Italia. Targeting HER2: Key points.
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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 --- Napoli, Italia
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
Adjuvant SettingWhat we know • Trastuzumab has changed the natural history of early HER2+ BC Year
Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countries No. of patients prevented from developing metastases Incidence of MBC without Herceptin Herceptin introduced 27,737 Patients,n 20,000 18,000 16,000 14,000 12,000 10,000 8000 6000 4000 2000 0 2000 2005 2010 2015 Year Weisgerber-Kriegl et al, ASCO 2008
More than 14.000 patients were recruited in 4 international clinical trials Docetaxel + carboplatin Docetaxel Trastuzumab Paclitaxel Standard CTx HERA (ex-USA) BCIRG 006 (global) Observation IHC / FISH (n=5,090) FISH(n=3,222) 1 year 1 year 2 years 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=2,030) IHC / FISH (n=3,505) 1 year 1 year 1 year Doxorubicin + cyclophosphamide IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006
Adjuvant settingWhat we do not know Small, node negative tumors are under represented in clinical trials
Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Results • Overall 7,164 pts. with pT1pN0 tumors • median follow-up 4.5 - 12.4 yrs.) • 600 pts. with HER-2 + tumors • % HER-2 + disease • rangingbetween 7 and 10% • Absoluterisksofdistantrelapse HER2+ • 5 yrs. ± 10-15% • 10 yrs. 22-28% • Increasedriskofdiseaserelapseif HER-2 + • hazardratiosrangingbetween 2.4 and 8.99 ReviewedbyOakman C et al, Educational book – ESMO meeting, Milan – October 2010
Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Caveats and Conclusions • Caveats - heterogeneity in adjuvanttherapies - HRs status notalwayscentrallyrevised - in 3 out of 7 studies pT1c tumorswereeligible - only 2 out of 7 studiesevaluateoutcomebycombinationof HER-2 and HRs status • “Take-home” messages - thereis a substantialdegreeofconcordance in considering HER-2 + patientswith pT1pN0 tumors at increasedriskofrelapsecomparedto the HER-2 negative population (2 to 9 foldincrease) ReviewedbyOakman C et al, Educational book – ESMO meeting, Milan – October 2010
Key question Is proportional benefit from adjuvant systemic therapies dependent on disease stage ?
Potential options for adjuvant treatment of endocrine-resistant pT1b pN0 tumors HER-2 + • Docetaxel-Cyclophosphamide (TC) x 4 + Trastuzumab* (lack of phase III data) • Docetaxel-Carboplatin-Trastuzumab (TCH) x 6 (BCIRG 006 data) Trastuzumab Trastuzumab * concomitant trastuzumab > sequential trastuzumab
Treatment decision: a multi-factorial process Tumor* : Size Vascularinvasion Ki-67 Patient: Co-morbidities Age Patient : Expectations Preferences Treatment decision
Adjuvant settingWhat we do not know Duration of Trastuzumab
Adjuvant trials with different duration of trastuzumab administration • HERA (PI M. Piccart): sample size ~34001 • 12 vs 24 months of H following adjuvant CT • Phare (PI X. Pivot): sample size ~34002 • 6 vs 12 months of H following adjuvant CT • Persephone (UK-NCRI): sample size ~40003 • 6 vs 12 months of H following adjuvant CT • Hellenic Oncology Group (Greece): sample size 4784 • 6 vs 12 months of H with ddDoc after FEC • SOLD (PI H. Joensuu): sample size ~30006 • HD 3-wkly x3 ->FE75C x3 • vs • HD 3-wkly x3 ->FE75C x3 -> H 3-wkly x14 • ShortHER(PI PF. Conte): sample size ~12505 • D 3-wkly x3 + H weekly x 9 -> FE60C x3 • vs • AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14
Overall Survival by Trastuzumab Treatment Groups 1.0 Negative No Trastuzumab Trastuzumab 0.8 HER2+ / Herceptin 0.6 OverallSurvivalProbability HER2- 0.4 HER2+ / No Herceptin 0.2 0.0 0 12 24 36 48 60 Monthsfrom Diagnosi
What we Know The first line
HERNATA study : results Overall Survival Time to Progression Andersson JCO 2010
HERNATA study: results Time to Treatment Failure Andersson JCO 2010
HERNATA study : safety profile Andersson JCO 2010
What we Know The second line
Tyverb plus capecitabine: significantly longer TTP in difficult to treat population (EGF100151, independent assessment) Tyverb + capecitabine Capecitabine HR: 0.57 (95% CI: 0.43, 0.77) p=0.00013 Cumulative progression-free (%) 18.6 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 lapatinibplus 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.
What we Know Beyond the second line
100 80 60 Cumulative progression-free (%) 6-month PFS 40 28% 20 13% 0 0 10 20 30 40 50 60 Time from randomisation (weeks) Subjects at risk: Lapatinib Lapatinib + trastuzumab 148 148 53 73 21 42 13 27 5 8 0 2 Lapatinib in combination with trastuzumab significantly prolonged PFS compared with lapatinib alone (EGF104900)
Updated overall survival in ITT (EGF104900) 100 80% 80 70% 60 Cumulative % alive without progression 56% 6 month OS 40 41% 20 L+T L 12 month OS 0 0 5 10 15 20 25 30 35 Time from randomization (months) Patients at risk L L+T 148 148 121 102 88 65 64 47 43 28 25 13 1
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 In vitro assays: Receptor expression, phosphorylation, signalling, tumour growth Treatment: lapatinib, trastuzumab, or both ErbB2-positive BC cells (SKBR3 and MCF7-HER2) Mouse xenograft Scaltriti et al., J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 3594 and poster Scaltriti et al., Oncogene 2009; www.nature.com/onco
What we Know HER2+ and HR+
HER2 and hormone receptor-positive BCClinical trials to assess therapy Cortes Nat Rev Clin Oncol 2010
HER2 and hormone receptor-positive BC Clinical trials to assess therapy 100 80 60 40 20 0 Combination with chemotherapy H0648g M77001 Overall response rates (%) Combination with Aromatase inhibitors EGF30008 TAnDEM 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. 8.10-12 Cortes Nat Rev Clin Oncol 2010
What else we Know The Future Trastuzumab + Pertuzumab
Pertuzumab and trastuzumab have complementary mechanisms of action Pertuzumab HER2 HER1/3/4 Trastuzumab Dimerizationdomain Subdomain IV • Trastuzumab: • Inhibits ligand-independent HER2 signaling • Activates ADCC • Prevents HER2 ECD shedding • Pertuzumab: • Inhibits ligand-dependent HER2 dimerization and signaling • Activates ADCC ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain
CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line setting Placebo + trastuzumab PD n=406 Docetaxel*≥6 cycles recommended Patients withHER2-positive MBCcentrally confirmed (N = 808) 1:1 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) • 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/m2, escalating to 100 mg/m2 if tolerated * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease
Primary endpoint: Independently assessed PFSn = 433 PFS events 100 Ptz + T + D: median 18.5 months ∆ = 6.1 months 90 Pla + T + D: median 12.4 months 80 70 60 50 Progression-free survival (%) 40 HR = 0.6295% CI 0.51‒0.75p<0.0001 30 20 10 0 0 5 10 15 20 25 30 35 40 Time (months) n at risk 406 311 209 93 42 17 7 0 0 Ptz + T + D 402 345 267 139 83 32 10 0 0 Pla + T + D Stratified by prior treatment status and region D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
Overall survival: Predefined interim analysisMedian follow-up: 19.3 months, n = 165 OS events 100 90 80 70 HR = 0.64*95% CI 0.47‒0.88p = 0.0053* 60 50 Overall survival (%) 40 30 Ptz + T + D: 69 events 20 Pla + T + D: 96 events 10 0 0 5 10 15 20 25 30 35 40 45 Time (months) n at risk Pertuzumab + T + D 406 383 347 228 143 67 24 2 0 0 Placebo + T + D 402 387 367 251 161 87 31 4 0 0 * The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
Cardiac tolerability * LVSD was defined as NYHA class III/IV LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
Adverse events (all grades)≥25% incidence or ≥5% difference between arms
Summary and conclusions CLEOPATRA met its primary endpointand 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-positivefirst-line MBC
What else we Know The Future T-DM1
Target expression: HER2 Monoclonal antibody: trastuzumab • Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) T-DM1 • Linker Systemically stable Breaks down in target cancer cell Trastuzumab emtansine (T-DM1): the first-in-class HER2-targeted antibody-drug conjugate
PDa PDa Study DesignTDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC • Randomized, phase II, international, open-label studyb • 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 HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) T-DM1 3.6 mg/kg q3w IV (n=67) 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m2 q3w (n=70) Crossover to T-DM1 (optional) aPatients were treated until PD or unacceptable toxicity. bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.
Progression-Free Survival by InvestigatorRandomized Patients 1.0 0.8 0.6 0.4 0.2 0.0 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Proportion progression-free 0 2 4 6 8 10 12 14 16 18 20 Time (months) Number of patients at risk T+D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 Hazard ratio and log-rank P value were from stratified analysis.
Duration of Response by InvestigatorPatients with Measurable Disease at Baseline with an Objective Response 1.0 0.8 0.6 0.4 0.2 0.0 Trastuzumab + docetaxel (n=40) T-DM1 (n=43) Proportion progression-free 0 2 4 6 8 10 12 14 16 18 Duration of objective response (months) Number of patients at risk T+D 40 40 38 32 19 8 2 1 1 0T-DM1 43 41 38 33 27 19 12 6 3 0 Kaplan-Meier estimates are shown. aNR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm.
Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patientsa Greenrepresents those AEs with ≥20% difference between treatment arms. aIn either treatment arm. bNo adverse events listed were grade 5. cTwo patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. dIncludes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. eNational 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.
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 • aBoth patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting. • bThis patient did not receive prior treatment with an anthracycline.
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
TDM4370g (EMILIA) Phase III Study: T-DM1 vsCapecitabine + 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 T-DM1 (3.6 mg/kg) q3w • HER2-positive LABC or MBC (N=980) • Previously received trastuzumab-based therapy 1:1 Lapatinib (1250 mg/day, days 1–21) + capecitabine (1000 mg/m2, days 1–14) q3w www.clinicaltrials.gov. NCT00829166.