Presentation on theme: "Targeting HER family receptors in breast cancer"— Presentation transcript:
1Targeting HER family receptors in breast cancer Prof. Sabino De PlacidoDip. di Endocrinologia ed Oncologia Molecolare e ClinicaUniversità Federico II --- Napoli, Italia
2Targeting 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 outcomeThe 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
3Adjuvant Setting What we know Trastuzumab has changed the natural history of early HER2+ BCYear
4Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countriesNo. of patients prevented from developing metastasesPatients, n20,000Incidence of MBC without HerceptinHerceptin introduced18,00027,73716,00014,00012,00010,00080006000400020002000200520102015YearWeisgerber-Kriegl et al, ASCO 20084
5More than 14.000 patients were recruited in 4 international clinical trials HERA (ex-USA)BCIRG 006 (global)ObservationIHC / FISH (n=5,090)FISH (n=3,222)1 year1 year2 years1 yearNCCTG N9831 (USA)NSABP B-31 (USA)IHC / FISH (n=3,505)IHC / FISH (n=2,030)1 year1 year1 yearDoxorubicin + cyclophosphamideDocetaxel + carboplatinStandard CTxDocetaxelTrastuzumabPaclitaxelIHC, immunohistochemistry FISH, fluorescence in situ hybridisationCTx, chemotherapyPiccart-Gebhart et al Romond et al 2005; Slamon et al 2006
9Adjuvant setting What we do not know Small, node negative tumors are under represented in clinical trials
10Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. ResultsOverall 7,164 pts. with pT1pN0 tumorsmedian follow-up yrs.)600 pts. with HER-2 + tumors% HER-2 + diseaseranging 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 8.99Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010
11Caveats “Take-home” messages - heterogeneity in adjuvant therapies Studies investigating clinical outcome of pT1pN0 tumors by HER-2 and hormone receptors (HRs) status. Caveats and ConclusionsCaveats- 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)Reviewed by Oakman C et al, Educational book – ESMO meeting, Milan – October 2010
12Key questionIs proportional benefit from adjuvant systemic therapies dependent on disease stage ?
13Potential 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)TrastuzumabTrastuzumab* concomitant trastuzumab > sequential trastuzumab
14Treatment decision: a multi-factorial process Tumor* :SizeVascular invasionKi-67Patient :Co-morbiditiesAgePatient :ExpectationsPreferencesTreatment decision
15Adjuvant setting What we do not know Duration of Trastuzumab
16Adjuvant trials with different duration of trastuzumab administration HERA (PI M. Piccart): sample size ~3400112 vs 24 months of H following adjuvant CTPhare (PI X. Pivot): sample size ~340026 vs 12 months of H following adjuvant CTPersephone (UK-NCRI): sample size ~40003Hellenic Oncology Group (Greece): sample size 47846 vs 12 months of H with ddDoc after FECSOLD (PI H. Joensuu): sample size ~30006HD 3-wkly x3 ->FE75C x3vsHD 3-wkly x3 ->FE75C x3 -> H 3-wkly x14ShortHER (PI PF. Conte): sample size ~12505D 3-wkly x3 + H weekly x 9 -> FE60C x3AC or EC x 4 -> HD or HP 3-wkly x4 -> H 3-wkly x14
21HERNATA study : results Time to ProgressionOverall SurvivalAndersson JCO 2010
22HERNATA study: results Time to Treatment FailureAndersson JCO 2010
23HERNATA study : safety profile In summary, the results from this randomized phase III trial of first-line therapy in HER2-positive MBC or LABC failed to demonstratesuperiority in terms of efficacy of docetaxel plus trastuzumab compared with vinorelbine plus trastuzumab.However, toxicity was much more pronounced with docetaxel, and thus vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balanceAndersson JCO 2010
25Cumulative progression-free (%) Tyverb plus capecitabine: significantly longer TTP in difficult to treat population (EGF100151, independent assessment)Tyverb + capecitabineCapecitabineHR: 0.57 (95% CI: 0.43, 0.77)p=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 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.
27Cumulative progression-free (%) Time from randomisation (weeks) Lapatinib in combination with trastuzumab significantly prolonged PFS compared with lapatinib alone (EGF104900)Subjects at risk:148LapatinibLapatinib + trastuzumab5373214213275826-month PFSCumulative progression-free (%)13%28%20406080100103050Time from randomisation (weeks)LapatinibLapatinib + trastuzumabn=145n=146Progressed or died, n128127Median, wks8.112.0HR (95% CI)0.73 (0.57, 0.93)p value0.008
28Updated overall survival in ITT (EGF104900) 100Ln=145L+Tn=146Died, n (%)113 (78)105 (72)Median, months9.514Hazard ratio (95% CI)0.74 (0.57, 0.97)Log-rank p value.02680%8070%60Cumulative % alive without progression56%6 month OS4041%20L+TL12 month OS5101520253035Patients at riskTime from randomization (months)LL+T14812110288656447432825131
29Lapatinib effect on ErbB2 accumulation at cell membrane: novel mechanism for enhanced effects of combined anti-ErbB2 therapyLapatinib has been shown to enhance antitumour effect of trastuzumab in vitro and in clinical studiesThis study explored the mechanism for this effect by investigating impact of lapatinib and trastuzumab on receptor expression and signallingTreatment:lapatinib, trastuzumab, or bothErbB2-positive BC cells (SKBR3 and MCF7-HER2)In vitro assays:Receptor expression, phosphorylation, signalling, tumour growthMouse xenograftScaltriti et al., J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 3594 and posterScaltriti et al., Oncogene 2009;29
32HER2 and hormone receptor-positive BC Clinical trials to assess therapy Cortes Nat Rev Clin Oncol 2010
33Overall response rates (%) HER2 and hormone receptor-positive BC Clinical trials to assess therapy10080604020Combination withchemotherapyH0648gM77001Overall response rates (%)Combination withAromatase inhibitorsEGF30008TAnDEMTrastuzumab+anastrozoleLapatinib+letrozoleTrastuzumab+paclitaxelTrastuzumab+docetaxelDrug regimenFigure 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 ratesCortes Nat Rev Clin Oncol 2010
34What else we KnowThe FutureTrastuzumab + Pertuzumab
35Pertuzumab and trastuzumab have complementary mechanisms of action HER2HER1/3/4TrastuzumabDimerization domainSubdomain IVTrastuzumab:Inhibits ligand-independent HER2 signalingActivates ADCCPrevents HER2 ECD sheddingPertuzumab:Inhibits ligand-dependent HER2 dimerization and signalingActivates ADCCADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain
36Pertuzumab + trastuzumab CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line settingPlacebo + trastuzumabPDn=406Docetaxel* ≥6 cycles recommendedPatients with HER2-positive MBC centrally confirmed(N = 808)1:1Pertuzumab + trastuzumabPDn=402Docetaxel* ≥6 cycles recommendedRandomization 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 discretionMBC, metastatic breast cancer; PD, progressive disease
37Primary endpoint: Independently assessed PFS n = 433 PFS events 102030405060708090100Ptz + T + D: median 18.5 months∆ = 6.1 monthsPla + T + D: median 12.4 monthsProgression-free survival (%)HR = % CI 0.51‒0.75 p<0.0001510152025303540Time (months)n at riskPtz + T + D402345267139833210Pla + T + D4063112099342177Stratified by prior treatment status and regionD, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
38Overall survival: Predefined interim analysis Median follow-up: 19 Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events100908070HR = 0.64* 95% CI 0.47‒0.88 p = *60Overall survival (%)504030Ptz + T + D: 69 events20Pla + T + D: 96 events1051015202530354045Time (months)n at riskPertuzumab + T + D40238736725116187314Placebo + T + D40638334722814367242* 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
39Cardiac tolerability Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407)Investigator-assessedsymptomatic LVSD*1.8%1.0%Independently adjudicated symptomatic LVSD*Fall in LVEF to <50% and by ≥10 percentage points from baseline6.6%3.8%* LVSD was defined as NYHA class III/IVLVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
41Summary 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 MBCMedian PFS increased by 6.1 months from 12.4 to 18.5 monthsThe 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 skinThese adverse events were primarily grades 1‒2, manageable, and occurred during docetaxel therapyThere was no increase in cardiac adverse events or LVSDThis new regimen may be practice-changing in HER2-positive first-line MBC
43Trastuzumab emtansine (T-DM1): the first-in-class HER2-targeted antibody-drug conjugate Monoclonal antibody: trastuzumabTarget expression: HER2Highly potent chemotherapy(maytansine derivative)Cytotoxic agent: DM1Systemically stableBreaks down in target cancer cellLinkerT-DM1
44HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) Study Design TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBCTrastuzumab8 mg/kg loading dose; 6 mg/kg q3w IV+ Docetaxel75 or 100 mg/m2 q3w(n=70)Crossover toT-DM1(optional)PDaHER2-positive, recurrent locally advanced breast cancer or MBC (N=137)1:1T-DM13.6 mg/kg q3w IV(n=67)PDaRandomized, phase II, international, open-label studybStratification factors: World region, prior adjuvant trastuzumab therapy, disease-free intervalPrimary end points: PFS by investigator assessment, and safetyData analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossoverKey secondary end points: OS, ORR, DOR, CBR, and QOLaPatients 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.
45Progression-Free Survival by Investigator Randomized Patients MedianPFS, mosHazard ratio95% CILog-rank P value18.104.22.16840.364–0.03531.00.80.60.40.20.0Trastuzumab + docetaxel (n=70)T-DM (n=67)Proportion progression-freeTime (months)Number of patients at riskT+DT-DMHazard ratio and log-rank P value were from stratified analysis.
46Duration of Response by Investigator Patients with Measurable Disease at Baseline with an Objective ResponseMedianDOR, mos95% CI9.5NRa6.6–10.6–1.00.80.60.40.20.0Trastuzumab + docetaxel (n=40)T-DM (n=43)Proportion progression-freeDuration of objective response (months)Number of patients at riskT+D T-DMKaplan-Meier estimates are shown.aNR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm.
47Trastuzumab + docetaxel (n=66)c Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of PatientsaAEAll grade, n (%)Grade ≥3b, n (%)Trastuzumab + docetaxel (n=66)cT-DM1 (n=69)c,dAlopecia44 (66.7)3 (4.3)eFatigue30 (45.5)34 (49.3)3 (4.5)Nausea29 (43.9)33 (47.8)2 (2.9)Diarrhea11 (15.9)2 (3.0)Peripheral edema7 (10.1)Increased AST4 (6.1)27 (39.1)6 (8.7)Pyrexia15 (22.7)1 (1.5)Headache12 (18.2)25 (36.2)Back pain20 (30.3)18 (26.1)1 (1.4)Increased ALT16 (23.2)Pneumonia4 (5.8)Green represents 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.
48Trastuzumab + docetaxel Cardiac SafetyCardiac function was assessed locally and centrally based on cardiac ECHO/MUGAPrior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectivelyAsymptomatic LV dysfunctionThere were no clinically significant cardiac events reportedLVEF assessmentTrastuzumab + docetaxelT-DM1Local assessmentPatients assessed6567Patients with post-baseline LVEF ≤40%2aCentral assessment601baBoth 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.
49Summary and Conclusions This is the first randomized study to evaluate an antibody-drug conjugate for HER2-positive MBCFirst-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 indexImproved PFS with T-DM1 may result from improved tolerability/duration of treatment/response and intrinsic potency of HER2-targeted DM1T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC
50TDM4370g (EMILIA) Phase III Study: T-DM1 vs Capecitabine + Lapatinib in HER2-Positive MBC T-DM1 (3.6 mg/kg) q3wHER2-positive LABC or MBC (N=980)Previously received trastuzumab-based therapy1:1Lapatinib (1250 mg/day, days 1–21)+ capecitabine (1000 mg/m2, days 1–14) q3wMulticenter, randomized, open-label studyTreatment continues until progressive disease/unacceptable toxicityPrimary end points: PFS by IRF, OS, 1-y and 2-y survival rates, SafetySecondary end points: PFS by INV, ORR, CBR, DoR, QOL, TTFNCT
51MARIANNE: Primary efficacy objective: Primary safety objective: Trastuzumab + taxane(n=364)HER2-positive progressive or recurrent locally advanced BC or previously untreated MBC(n=1092)T-DM1 + pertuzumab(n=364)T-DM1 + placebo(n=364)Primary efficacy objective:PFS assessed by an independent review facilityPrimary safety objective:To compare the safety of T-DM1 + pertuzumab or T-DM1 + placebo vs trastuzumab + taxaneBC = breast cancer; MBC = metastatic breast cancer; PFS = progression-free survival