Enfermedad con sobreexpresión de HER2

Enfermedad con sobreexpresión de HER2 Sònia Servitja Hospital del Mar. Barcelona

Índice ADYUVANCIA NEOADYUVANCIA CMM BIOMARCADORES SOPORTE

Índice ADYUVANCIA Los clásicos Trastuz subcutáneo Neratinib NEOADYUVANCIA CMM BIOMARCADORES SOPORTE

Her2+. ADYUVANCIA Los clásicos... Actualización a 10 años (SABCS 2015) HERA: DFS DFS benefits are seen regardless of the HR status Jackisch C, et al. SABCS 2015 (Poster PD5-01) BCIRG 006: DFS No statistical advantage of AC TH over TCH Slamon D, et al. SABCS 2015

Her2+. ADYUVANCIA Los clásicos... Actualización a 10 años (SABCS 2015) HERA: OS Significant, sustained and stable DFS & OS benefits for 1 year of TTZ Jackisch C, et al. SABCS 2015 (Poster PD5-01) BCIRG 006: OS DFS and OS data show a sustained and significant efficacy advantage of AC-TH and TCH Slamon D, et al. SABCS 2015

Her2+. ADYUVANCIA Trastuzumab subcutáneo. SafeHER 2577 patients Treatment: 1537 adj TTZ concurrent chemo 804 adj TTZ and sequential chemo 232 received TTZ and no chemo 44 Neoadjuvant TTZ SafeHer confirms the safety and tolerability of TTZ sc 600 mg fixed dose for 1 year as adjuvant therapy with concurrent/sequential chemo for HER2-positive ebc Gligorov J, et al. EBCC 2016 (Poster 326)

Her2+. ADYUVANCIA Neratinib: ExteNET Median relative dose intensity: 82% in the neratinib group and 98% in the placebo group. 2-year incidence of CNS recurrences: 0.91% in the neratinib group and 1.25% in the placebo group (p=0 44).

Her2+. ADYUVANCIA ExteNET: idfs 2y 93.9% 91.6% (months) 3 6 9 12 15 18 21 24 Chan A, Lancet Oncol 2016

Índice ADYUVANCIA NEOADYUVANCIA KRISTINE*: T-DM1+PTZ ADAPT * RH(+):T-DM1 + Ht / RH(-):Taxol TTZ+PTZ NSABP-B41*: Lapa NSABP-BF7: neratinib Dose dense doxorrubicin Non-pegilated liposomal doxorrubicin CMM BIOMARCADORES SOPORTE * Presentado por la Dra. Laura Murillo el viernes 17/06/16 en la sesión II: avances en neoadyuvancia

Her2+. NEOADYUVANCIA KRISTINE: pcr 56% TCHP vs 44% T-DM1+Pertu Favorable safety profile of T-DM1 + P with lower incidence of SAE and grade 3 AEs ADAPT Her2+/HR+: 41.5% pcr with ET + T-DM1 vs 41% with TDM-1 NSABP-B41: Dual blokade TTZ+Lapa and OS pcr 62%, but not superior to TTZ for RFI

Her2+. NEOADYUVANCIA APAPT Her2+/HR N=143 55-60% cn0 Nitz U, et al. ASCO 2016 100 90 80 70 60 50 40 30 20 10 0 78.6 ypt0/is ypn0 ypt0ypn0 33.7 24.4 PTZ+TTZ 90.5 PTZ+TTZ+Pacli

Her2+. NEOADYUVANCIA NSABP-BF7: Neratinib Diarrhea 70-90% of patients, 28-40% diarrhea grade 3 Dose reduction 26.4%, discontinuation 16.8% Jacobs SA, et al. SABCS 2015

Her2+. NEOADYUVANCIA Dose dense AC N=60 ddac THP from september 2013 to march 2015 1.6% pts experienced NYHA class III heart failure during the neoadjuvant phase pcr 100 ypt0/is ypt0 ypn0 80 60 78 66 85 100 77 85 70 50 43 40 20 0 Singh JC, et al. SABCS 2015 HR+ HR- Overall

Her2+. NEOADYUVANCIA NPL doxorrubicin N= 42 from april 2013 to January 2015 Myocet 50-60mg/m2 + Docetaxel 75mg/m2 + TTZ + PTZ x 6 cycles pcr 100 80 60 40 20 0 95 76 57 Overall Egle D, et al. SABCS 2015 RH+ RH-

HER2+. CMM HERITAGE PHEREXA TH3RESA SAPPHIRE: seguridad combinación PTZ + TTZ sc PERUSE: seguridad TTZ+PTZ +Taxanos (doce, pacli, nab-pacli) T-DM1 después de 1ªL con TTZ+PTZ Fase Ib/IIa T-DM1+ Doce +/- PTZ LUX 3 breast M1 SNC: neratinib lapatinib T-DM1

Her2+. CMM Confirm similar safety, efficacy and immunogenicity if ORR 69% at week 24 Results week 24 MYL1401O + taxane (n 230) Herceptin + taxane (n 228) ORR 69.6% 64% Difference (95CI) 5.53 (-3.08, 14.04) Efficacy equivalence based on ratio ORR and difference on ORR Rugo HS, et al. ASCO 2016

Her2+. CMM PHEREXA: PTZ en 2ªL Phase III, TTZ + Cape vs TTZ + Cape + PTZ who progressed to TTZ Stratification: prior CNS disease; mesurable vs no mesurable; response to 1 st L TTZ 25% previous neo/adj TTZ and 1st L 21-27% the duration of TTZ in 1st L was <6 months Urruticoechea A, et al. ASCO 2016

Her2+. CMM PHEREXA: PTZ en 2ªL PFS OS Statistical significance cannot be claimed due to hierarchiacal testing of OS after the primary PFS endpoint Urruticoechea A, et al. ASCO 2016

Her2+. CMM TH3RESA: T-DM1 en pre-tratadas (N=600) T-DM1 3.6 mg/kg q3w IV 2 prior HER2-directed therapies for advanced BC 2 Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice PD T-DM1 PD (optional crossover) 80.4% TTZ containing Tt Characteristic TPC (n=198) T-DM1 (n=404) Number of prior Chemo regimens for abc: Median (range) 3, % 4 5, % >5, % 4 (1 19) 39.4 32.8 27.8 4 (1 14) 32.6 37.1 30.3 13.6 9.9 Brain metastasis at baseline, % Wildiers H, et al. SABCS 2015

Her2+. CMM TH3RESA: OS Wildiers H, et al. SABCS 2015

Her2+. CMM T-DM1: después de 1ª L PTZ + TTZ 82 patients received T-DM1 after TTZ and PTZ 32% received T-DM1 as 1st or 2nd L 48% received it as 4th L or later. Duration on therapy 6months 30.8% Tumor response 17% Dzimitrowicz H, et al. JCO 2016

Her2+. CMM / CMLA Fase Ib/IIa: T-DM1 + Doce ± PTZ Metastatic BC: Doses: T-DM1 3.6 mg/kg + Doce 60 mg/m2 ORR 80% (20/25; 95% CI 59.3-93.2) Median PFS 13.8 months ( 1.6-33.5m) LABC: Doses: T-DM1 3.6 mg/kg + Doce 100 mg/m2 T-DM1 3.6 mg/kg + Doce 75mg/m2 + PTZ pcr (ypt0/is, ypn0) 60.3% (44/73; 95% CI 48.1-71.5) 50% of patients experienced adverse events requiring dose reductions Martin M, et al. Ann Oncol 2016

Her2+. CMM M1 cerebrales LUX-breast 3 Cortés J, et al. Lancet Oncol 2015 VRL + Afatinib vs afatinib vs treatment investigator s choice for brain mets No difference in patinets benefit but more toxicity TBCR022 Freedman RA, et al. JCO 2016 Progression to CNS-directed therapy. Neratinib 240mg bid Low activity (mpfs 1.9m). 21% diarrhea grade 3. Worse QoL T-DM1: retrospective analysis of 39 pts with BM Jacot W, et al. Breast C Res Treat 2016 44 % PR, 59 % clinical benefit rate. Median PFS 6.1 m (95 %CI 5.2 18.3), PFS 1y 33%, PFS 2y 17 %.

Her2+. CMM CLEOPATRA: the use of >6 D cycles compared with 6 D cycles does not provide a statistically significant PFS or OS benefit Milles D, et al. SABCS 2015 EMILIA: Final analysis OS, follow-up 48m Diéras V, et al. SABCS 2015

Her2+. BIOMARCADORES PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab S. Loibl. Ann Oncol 2016 Molecular alterations and Everolimus efficacy in human epidermal growth factor receptor 2-overexpressing MBC: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3 F. André. JCO 2016 Patients with wtpik3ca, normal PTEN or normal PI3K pathway activity did not derive PFS benefit from everolimus PTEN PIK3CA PI3K pathway

Her2+. BIOMARCADORES Higher sher2 values independently predict lapatinib PFS benefit (HR per 10ng/mL increase in sher2: lapatinib-containing therapies, 1.017 vs nonlapatinib-containing therapies, 1.041; P interaction =.008). Higher sher2 predicts greater PFS benefit with lapatinib independent of ther2 status. High sher2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies.

Her2+. SOPORTE CARDIOTOXICIDAD

Her2+. SOPORTE Diarreas por PTZ Mainly low grade Occurred most often in the first cycle Related study drug delays (<8%) or discontinuations (<2%) were uncommon. Overlap of diarrheal episodes with febrile neutropenia was infrequent, and did not increase with age Overall incidence of diarrhea Swain S, et al. SABCS 2015

Her2+. CONCLUSIONES Se mantiene el beneficio en DFS y OS de TTZ adyuvante un año TTZ subcutáneo es seguro y eficaz, equivalente a TTZ endovenoso administrado con Qt (estudio SafeHER) y con PTZ (estudio Sapphire) Biosimilar de TTZ equivalente a Herceptín en ORR y diferencia absoluta (requerimiento EMEA) Se posicionaran con fuerza? No es generalizable a otros escenarios Neratinb durante un año, después de tto con TTZ, demuestra un beneficio en idfs a 2 años del 2.3% (HR 0.67)

Her2+. CONCLUSIONES En neoadyuvancia, el doble bloqueo con trastuzumab y pertuzumab es el que aporta mejor relación entre pcr y toxicidad. La tasa de pcr global con doble bloqueo es >60%, pudiendo llegar al 95% en RH(-). Pertuzumab en 2ª línia no demuestra beneficio en DFS, pero hay un incremento de OS de 8 meses. T-DM1 sigue demostrando beneficio en OS en 2ªL y en sucesivas, y después de 1ªL con TTZ+PTZ En M1 cerebrales: Afatinib y neratinib no han demostrado beneficio. T-DM1 seguro y activo.

MUCHAS GRACIAS sservitja@hospitaldelmar.cat