Enfermedad con sobreexpresión de HER-2 neu

Transcription

1 Enfermedad con sobreexpresión de HER-2 neu Elsa Dalmau Parc Taulí Sabadell. Hospital Universitari.

2 Enfermedad con sobreexpresión de HER-2 neu ÍNDICE Neoadyuvancia Adyuvancia Enfermedad avanzada

3 Enfermedad con sobreexpresión de HER-2 neu ÍNDICE Neoadyuvancia Neo-ALTTO Biomarcadores Her2+/RH+ Adyuvancia Enfermedad avanzada

4 Neoadyuvancia EFS shown for the ITT population OS shown for the ITT population

5 Neoadyuvancia Landmark analyses shown for the interaction between pcr and EFS in the ITT population Landmark analyses shown for the interaction between pcr and OS in the ITT population De Azambuja, Lancet Oncol 2014

6 Neoadyuvancia PFS by tpcr: all treatment arms combined, ITT population Gianni, ASCO 2015, Abst 505

7 NeoALTTO 1 pcr was lower for patients with PI3KCA mutations. The difference was stadistically significant in the combination arm. EFS and OS not affected by PI3KCA status GeparQuattro, GeparQuinto and GeparSixto 2 The presence of a PI3KCA mutation was significantly associated with a lower pcr rate. The association was statistically significant in the G6 study (OR 0.357) in which patients received a dual anti-her2 treatment. The HR +/ HER2 + tumors harboring the PI3KCA mutation have the lowest pcr in the dual anti-her2 treatment arm. Neither DFS nor OS are statistically significantly different between pts with or without a PI3KCA mutation. CHER-LOB 3 Neoadyuvancia. Biomarcadores. PI3KCA WT status is related to a higher pcr rate following CT + dual blockades with T + L PI3KCA mutational status does not predict any differential sensitivity to CT + either T or L 1 Majewski, JCO 2015 (Baselga, ECCO 2013), 2 Loibl, JCO 2014 (Loibl, SABS 2013), 3 Guarneri, ESMO 2014

8 Neoadyuvancia. Biomarcadores. Presented By Sibylle Loibl at 2015 ASCO Annual Meeting

9 Neoadyuvancia. Biomarcadores. pcr Rates According to PI3KCA Mutation Status Overall and by HR Status pcr Rates According to PI3KCA Mutation Status Overall and by anti-her2 Treatment Loibl, ASCO 2015

10 Neoadyuvancia. Biomarcadores. Disease Free Survival HR-ve HR+ve Loibl, ASCO 2015

11 Enfermedad con sobreexpresión de HER-2 neu ÍNDICE Neoadyuvancia Adyuvancia Tumores pequeños Duración trastuzumab Tratamiento extendido Enfermedad avanzada

12 Adyuvancia. Tumores pequeños. SABCS 2013 DFS event Patients (N=406) Any recurrence or death 3% Local/regional Recurrence Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+) 0.7% 0.2% Distant recurrence 0.4% New contralateral BC 0.9% Death Non-breast cancer related 0.5%

13 Adyuvancia. Tumores pequeños. Probabilites of Disease-free Survival and Recurrence-free Interval 3-year DFS 98.7% P< year RFS 99.2% P<0.001 Tolaney, NEJM 2015 Limitations!! Lack of randomization Inclusion of T1a tumors 67% HR+ tumors (recurrence expectance beyond de time of follow-up)

14 Adyuvancia PLANNED JOINT ANALYSIS OF OVERALL SURVIVAL FROM NSABP B-31 AND NCCTG N year incidence rate of deaths by cardiac causes: 0.2% (Trastuzumab regimen) and 0.1% (control arm)

15 Adyuvancia Cardiac toxicity was lower in lapatinib arm but low in all treatment arms The HR >1 was observed independent of hormone receptor status of the tumor Patients who received trastuzumab had a 33% reduction in the hazard of a DFS event. - HR 0.67, 95%CI ( ) 2% pts with SNC metastasis as a first site of recurrence in all subgroups of treatment ESMO 2014, Abst LBA7

16 Adyuvancia. Duración trastuzumab. Six versus twelve months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: A multicenter randomized study by the Hellenic Research Group (HORG) Mavroudis, Annals of Oncol pts with Early BC Her y Node-positive or high risk node-negative S U R G E R Y Primary endpoint: DFS Secondary endpoints: OS and toxicity Epirubicin 75mg/m2 + Cyclophosphamide 700mg/m2 + 5-fluouracil 700mg/m2 every 2w x 4 cycles Docetaxel 75mg/m2 + Trastuzumab 4mg/kg every 2w Trastuzumab 6mg/kg every 3w x 6 m Trastuzumab 6mg/kg every 3w x 12 m 3-year DFS 95.7% (12m) and 93.3% (6m), p=0.436 HR 1.57 (95%CI ); p=0.137

17 Adyuvancia. Tratamiento extendido. PATIENT AND TUMOR CHARACTERISTICS 46% premenopausal 37% sequential trastuzumab 76% positive nodes 68% (Neo)Adjuvant chemotherapy with antracycline + taxane Chan, ASCO Abst 508

18 Adyuvancia. Tratamiento extendido. Neratinib Placebo Chan, ASCO Abst 508

19 Adyuvancia. Tratamiento extendido. Neratinib Neratinib Placebo Placebo Chan, ASCO Abst 508

20 Adyuvancia. Tratamiento extendido. Grade 3: median duration 5 days Most occurred <30 days Drug discontinuation 16.8% No differences in LVEF 2 (N1.3% vs Pl 1.1%) Incidence of cardiac AEs similar in both arms Chan, ASCO Abst 508

21 In summary... Adyuvancia For patients with HER2+ small tumors the use of a less aggressive scheme of treatment with paclitaxel + trastuzumab achieves a low rate of cancer recurrence. Should adjuvant CT with trastuzumab be considered in all patients with small, node-negative tumors? T1a and T1b? Which is the best (safest and most effective) regimen of treatment for these patients? 1 year of adjuvant trastuzumab remains the current standard of care 2 years of trastuzumab offers no additional efficacy but increase toxicity (HERA trial) 6 months of trastuzumab have NOT meet the non-inferiority criteria vs 12 months of trastuzumab (PHARE and HORG trials) Neratinib improves idfs at the 2 year landmark analysis We need longer F/U data to confirm sustained benefit and OS results. Benefit or neratinib appears greater in ER+. For lower risk patients, does the toxicity justify the small potential benefit? Pertuzumab is an option in the neoadjuvant (adjuvant?) setting for high risk patients, so would the neratinib benefit still persist in this group?

22 Enfermedad con sobreexpresión de HER-2 neu ÍNDICE Neoadyuvancia Adyuvancia Enfermedad avanzada 1ª línea Líneas posteriores Nuevos fármacos M1 SNC

23 Enfermedad avanzada. Primera línea. Lapatinib or Trastuzumab Plus Taxane Therapy for HER-2 Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31 Gelmon, JCO m 11.3m Kaplan-Meier estimates of intention-to-treat progression-free survival Kaplan-Meier estimates of intention-to-treat overall survival

24 Enfermedad avanzada. Primera línea. Swain, ESMO 2014 Swain, NEJM 2015

25 Enfermedad avanzada. Primera línea. CLEOPATRA Study Design n = 406 Placebo + trastuzumab PD HER2-positive MBC centrally confirmed (N = 808) Primary endpoint PFS 1:1 Docetaxel* 6 cycles Pertuzumab + trastuzumab PD n = 402 Docetaxel* 6 cycles Randomization stratified by geographic region and neo/adjuvant chemotherapy Study dosing q3w: Pertuzumab/placebo: 840 mg loading 420 mg maintenance Trastuzumab: 8 mg/kg loading 6 mg/kg maintenance Docetaxel: 75 mg/m mg/m 2 escalation if tolerated * < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretion. Interval 12 months between neo(adjuvant) therapy and metastatic diagnosis was required

26 OS (%) Enfermedad avanzada. Primera línea. Final OS Analysis Median follow-up 50 months (range 0 70 months) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) months Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months Swain, ESMO 2014

27 Enfermedad avanzada. Primera línea. AEs with 25% incidence or 5% difference between groups: Diarrhea Rash Mucosal Inflammation Pruritus Febril neutropenia Dry skin Headache Upper respiratory tract infection Muscle spasms Left ventricular disfunction rate 6.6% (P) vs 8.6% (No P) Swain, NEJM 2015

28 Enfermedad avanzada. Primera línea. Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study Presented By Paul Ellis at 2015 ASCO Annual Meeting

29 Enfermedad avanzada. Primera línea MARIANNE Study Design 363 Ellis, ASCO 2015

30 Enfermedad avanzada. Primera línea. Progression-Free Survival by IRF ORR: HT 67.9%, T-DM1 59.7%, T-DM1+P 64.2% DURATION OF RESPONSE: HT 12.5m, T-DM1 20.7m, T-DM1-P 21.2m Ellis, ASCO 2015

31 Enfermedad avanzada. Primera línea. Maintenance of Health-Related Quality of Life Ellis, ASCO 2015

32 Enfermedad avanzada. Primera línea. Ellis, ASCO 2015

33 Enfermedad avanzada. Primera línea. Hurvitz S6-01, SABCS 2014

34 Enfermedad avanzada. Primera línea. Prespecified was <0.0044

35 Enfermedad avanzada. Múltiples líneas. TRASTYVERE: A Retrospective Analysis of Heavily Pretreated HER2-Positive MBC Patients treated in Spain with Lapatinib plus Trastuzumab as Compassive Therapy J Gavilá, SABCS 2014 (P ) HER2+ metastatic or locally advanced BC ECOG status 0 2 Progression 1 prior line of trastuzumab for advanced disease Concomitant endocrine therapy, brain M1 and/or prior exposure to L was allowed. L+T (n=115) Median age (range) 60 (34-89) RE Negative, % 36% Prior lines of Trastuzumab 3 Prior treatment wih Lapatinib, % 64 Visceral disease, % SNC MTS, % Lapatinib + Trastuzumab Primary outcome: Clinical Benefit Rate Secondary outcomes: TTP, OS, toxicity CBR 35% (95%CI, 26-44%) 6 CR, 19 PR, 15 SD 24w CBR L naïve 41.5% CBR L pretreated 31.5% p=0.285 CBR HR- 39% CBR HR+ 32.9% p=0.509 TTP 3.91m (95%CI ) OS 21.6m (95%CI )

36 Enfermedad avanzada. Otros fármacos. Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic HER2-Positive Breast Cancer Saura, JCO 2014 Phase I/II, open-label, two-part study. PART ONE: Modified 3+3 dose-escalation study to define the MTD of neratinib + capecitabine in pts with advanced solid tumors. Neratinib 240mg/d vo + lapatinib 1500mg/m2/d PART TWO: Efficacy and safety of the MTD of neratinib + capecitabine in pts with advanced HER2-positive BC Best OR to Study Treatment (part two evaluable for efficacy population; n=68) Response ORR (63%) CR PR No prior Lapatinib (n=61) 64% 12% 53% Prior Lapatinib (n=7) 57% 14% 43% CBR 72% 71% Grade 3/4 AEs: diarrhea 26%, PPE 14%, asthenia 4%, vomiting 4%, elevated AST 3% PFS 40.3w PFS in pts with no prior lapatinib treatment

37 Enfermedad avanzada. M1 SNC. CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With HER2-Positive MBC Pivot, JCO 2015 Study design Primary endpoint: incidence of CNS M1 as site of first relapse (in the M-ITT population) Only 475 pts included Closed prematurely on June 2011 CNS as first site of relapse 3% lapa+cape 5% trastu+cape OR 0.65, p.360 Overall incidence of CNS progression 7% lapa+cape 6% trastu+cape p.8646

38 Enfermedad avanzada. M1 SNC. CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With HER2-Positive MBC Pivot, JCO 2015 Progression-free survival in the ITT population Progression-free survival in patients previously treated with trastuzumab

39 Enfermedad avanzada. M1 SNC. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Krop, Annals of Oncology 2015 Progression-free survival according to independent review committee Overall survival 2% and 0.7% of pts withouth M1 at baseline developed CNS progression in the TDM-1 and XL arms 22.2% and 16% of pts with M1 at baseline developed CNS progression in the TDM-1 and XL arms

40 Enfermedad avanzada Unanswered questions... Although better tolerated, T-DM1 or T-DM1+P are not superior to TH, so THP remains the preferred first-line therapy for HER2+MBC. Can we extrapolate the same results with THP for high risk patients who will receive pertuzumab in the neoadjuvant (adjuvant) setting? Are the results of these trials applicable for patients developing metastatic disease after adjuvant treatment with trastuzumab? And the duration of targeted therapy for those responding? Can we combine Pertuzumab and Trastuzumab with other partners? Other taxans? (PERUSE) Other chemotherapies? VNR? (VELVET, ORR 62.9 and 64%) Other biologics? TDM1? (MARIANNE negative)

41 Enfermedad avanzada Unanswered questions... T-DM1 has been established as a second-line or first-line in early relapse demonstrating superiority in front of capecitabine + lapatinib. Has T-DM1 the same benefit in second-line setting in patients who have received pertuzumab and trastuzumab previously? Could neratinib replace lapatinib in the combination with capecitabine keeping in mind its toxicity? Trastuzumab + lapatinib might be an option from the third-line and beyond. Have we to restrict this treatment only for patients with HR negative? After treatment with a trastuzumab-containing regimen, 10-15% of patients will develop CNS metastases despite systemic control. Which the best treatment for these patients?

42 Enfermedad avanzada TREATMENT SCHEME Seah, JNCCN st line Docetaxel + Trastuzumab + Pertuzumab Early relapse TDM1 2nd line TDM1 3rd line Capecitabine + Lapatinib QT + Trastuzumab Lapatinib + Trastuzumab TDM1 4rd line and beyond QT + Trastuzumab Capecitabine + Lapatinib Lapatinib + Trastuzumab TDM1

43 Muchas gracias