Estado del arte enla enfermedadprecoz: Neoadyuvancia.

Avanzando en cáncer de mama HER2+: un presente que nos acerca al futuro Estado del arte enla enfermedadprecoz: Neoadyuvancia. Dra. Sònia Servitja Servicio de Oncología Médica

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 2. TDM1 III. CONCLUSIONS

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 2. TDM1 III. CONCLUSIONS

pcr WITHOUT TRASTUZUMAB pcr in Her2(+) patients treated with neoadjuvant chemo without trastuzumab 23.5% (12/51) DFS Penault-Llorca, Oncolgist 2007

pcr WITH TRASTUZUMAB pcr (%) 47,9 26 38 55 54,5 0 10 20 30 40 50 60 GEICAM 2006-14 Pierga, 2010 NOAH Z1041 Buzdar, 2007

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 1) Lapatinib 2) Neratinib 3) Pertuzumab 2. TDM1 III. CONCLUSIONS

DUAL BLOCK: TTZ + LAPATINIB STUDY (n) NeoALTTO 1 (n 455) NSABP B-41 2 (n 519) CALGB 40601 3 (n 299) CHER-LOB 4 (n 121) TRIO B07 5 (n 128) TREATMENT Pacli +T/L AC Pacli+T/L Pacli +T/L Pacli+T/L FEC T/L Doce- Carbo-T/L %pcr TTZ %pcr LAPATINIB %pcr TTZ+LAPA DISCONTINUATION (TL vst) 27.6 20 46.8 39.5 vs 8 49.4 47.4 60.2 37 vs 22 43 29 52 NR 25 26.3 46.7 17 vs 0 47 25 51 21 vs 0 1. Baselga J, Lancet 2012 2. Robidoux A, Lancet Oncol 2013 3. Carey L, ASCO 2013. Abstract 500 4. Guarneri V, J ClinOncol2012 5. Hurvitz S, SABCS 2013. Abstract S1-02.

DUAL BLOCK: TTZ + LAPATINIB PAMELA 18 weeks Her2+ BC stage I-IIIA TRASTUZUMAB/3w + LAPATINIB 1000mg/d + LET/TMX (HR+) surgery AdjsistemicTt at physician decision Baseline PAM50 Week2 PAM50 N 150. Medianf-up 31 m Week6 Ultrasound 1 ry EP: Abilityof Her2-enrich to predictpcr(tis-0) TRASTUZUMAB + LAPATINIB + PACLITAXEL 2 ry EP: pcrbreastandaxilla(tpcr), associationbaselinesubtypewithpcr, changesin subtype (baseline vs w2) PD Patientcharact.: 8% T3, 65% cn0, 51% HR+ Prat A, Lancet Oncol 2017

DUAL BLOCK: TTZ + LAPATINIB PAMELA: Heterogeneity of Her2+ disease At 2weeks: Normal-like, L-A Her2-E, L-B = Basal Prat A,SABCS 2016 & Lancet Oncol 2017

DUAL BLOCK: TTZ + LAPATINIB PAMELA: Her2-E higher pcr and tpcr Prat A, SABCS 2016 & LancetOncol2017

DUAL BLOCK: TTZ + LAPATINIB 1. Toxicity(diarrheaLTD) [1-6] 2. LapatinibalonelesspCRthantrastuzumab [1-6] 3. NeoALTTOstudy:nodifferencesinDFSandOS [5] ALTTOstudy:adjuvantlapatinib+trastuzumabnodifferencesinDFS [6] 4. No evidence to support the use of lapatinib in the neo/adjuvant setting 1. Guarneri V, J Clin Oncol 2012 2. Baselga J, Lancet 2012 3. Carey L, ASCO 2013. Abstract 500 4. Hurvitz S, SABCS 2013. Abstract S1-02 5. Piccart-Gebhart M, SABCS 2013. Abstract S1-01 6. Piccart-Gebhart M, ASCO 2014. Abstract LBA4.

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 1) Lapatinib 2) Neratinib 3) Pertuzumab 2. TDM1 III. CONCLUSIONS

DUAL BLOCK: TTZ + NERATINIB NSABP-BF7 Jacobs SA, et al. SABCS 2015

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

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 1) Lapatinib 2) Neratinib 3) Pertuzumab 2. TDM1 III. CONCLUSIONS

DUAL BLOCK: TTZ + PERTUZUMAB NEOSPHERE trial 1 ry endpoint: pcr(ypt0/is) Gianni L, Lancet Oncol 2012

DUAL BLOCK: TTZ + PERTUZUMAB NEOSPHERE trial Pathologic complete response (%) 100 90 80 70 p = 0.0063 60 tpcr 17.8% 39.3 50 40 21.5 30 17.7 11.2 20 10 0 T + D Ptz + T + D Ptz + T Ptz + D Gianni L, Lancet Oncol 2012

DUAL BLOCK: TTZ + PERTUZUMAB NEOSPHERE trial: PFS according to pcr 100 PFS, % 90 80 70 60 50 40 30 20 10 0 No RCp RCp n=323 n=94 5-year PFS, % (95% CI) 76 (71 81) 85 (76 91) HR (95% CI) 0.54 (0.29 1.00) 0 12 24 36 48 60 Meses RCp No RCp Gianni L, Lancet Oncol 2012

DUAL BLOCK: TTZ + PERTUZUMAB NEOSPHERE trial: 5y PFS 86% vs 81% (HR 0.69) Gianni L, ASCO meeting 2015

DUAL BLOCK: TTZ + PERTUZUMAB TRYPHAENA trial 1 ry endpoint: cardiotoxicity 2 ry endpoint: pcr Schneeweiss A, Ann Oncol. 2013

DUAL BLOCK: TTZ + PERTUZUMAB TRYPHAENA trial Cardiacevents*(%) FEC-HP DHP * 10% FEVI asintomálca FEC DHP TCH-P Neoadj Tt 6 1 3 Total 7 8 8 90 80 70 60 50 40 30 20 10 0 FEC+HP- THP FEC-THP pcr TCHP ITT RH (+) RH (-) Schneeweiss A, Ann Oncol. 2013

DUAL BLOCK: TTZ + PERTUZUMAB Breast pcr 100 90 NOAH NeoSphere 4 cycles TRYPHAENA full chemotherapy + dual antibody therapy Pathologic complete response (%) 80 70 60 50 40 30 20 10 19% Δ 19 38 16.8% Δ 29 45.8 15-20% Δ 61.6 41.0 57.3 66.2 0 CT alone CT + T T+D Ptz+T+D Ptz+T+FEC FEC TCH+Ptz Ptz+T+D Ptz+T+D x6 Gianni, Lancet 2010; Gianni, Lancet 2012; Schneeweiss, Ann Oncol 2013

DUAL BLOCK: TTZ + PERTUZUMAB GEPARSEPTO trial RCp 66,7% 74,6% Untch, SABCS 2014 & Lancet Oncol 2016

DUAL BLOCK: TTZ + PERTUZUMAB ADAPT Her2+/RH- Nitz U, ASCO 2016

DUAL BLOCK: TTZ + PERTUZUMAB AC dose-dense (n=44) (n=13) (n=57) Singh JC, SABCS 2015 & Oncologist 2017

DUAL BLOCK: TTZ + PERTUZUMAB NON-PEGYLATED LIPOSOMAL DOXO Egle D, SABCS 2015

pcr increases when we use dual Her2 blockade and longer chemotherapy regimens Von Minckwitz, Cancer Network 2012

Qt+TTZ+PTZ: more pcr, Tt completion, and fewer toxicity Nagayama, JNCI 2014

DUAL BLOCK: TTZ + PERTUZUMAB COST-EFFECTIVE STUDY OF NEOADJUVANT PERTUZUMAB NeoSphere data Estimated benefit: prevention of 5% relapses at 5 years Endpoint: cost-utility of Doce-HP vs Doce-H D-HP gainqualys0.56 andsavings7230 Probablilistic sensitivity analyses D-HP was cost-effective at a threshold of 30000 Colomer, Value Health Journal 2016

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 2. TDM1 III. CONCLUSIONS

DUAL BLOCK: TDM1 + PERTUZUMAB KRISTINE trial: TTZ-PTZ vs TDM1-PTZ Hurvitz S, ASCO 2016

TDM1 vsttz Harbeck N, ASCO 2015

Outline I. STANDARD TREATMENT: Trastuzumab II. WHAT IS NEW? 1. Dual anti-her2 treatment 2. TDM1 III. CONCLUSIONS

CONCLUSIONES 1 Tto neoadyuvante con doble bloqueo Her2 aumenta la tasa de RCp La tasa de pcr global con doble bloqueo es >60%, pudiendo llegar al 95% enrh(-) 2 MayortasadeRCpalañadirpertuzumabatrastuzumabyconpautasdeTto más largas 3 La combinación de quimioterapia + trastuzumab + pertuzumab es la que obtiene mayor tasa de RCp con mejor perfil de toxicidad 4 Lapatinib o neratinib no indicado como parte del Tto neoadyuvante 5 PAM50 puede identificar subtipo HER2enriched, que obtiene mayor tasa de RCpconesquemessinQt

PREGUNTAS POR RESPONDER 1. Pertuzumab en neoadyuvancia, ha llegado para quedarse? 2. Podemos identificar pacientes que no necesitan doble bloqueo? 3. Que esquema de tratamiento es el óptimo? FEC-TTZ-PTZ x 3 Doce-TTZ-PTZ x3 AC x 4 Doce/Pacli-TTZ-PTZ TCH-Pertu ddac Pacli-TTZ-PTZ

PREGUNTAS POR RESPONDER 4. Podemos extrapolar la experiencia de Tolaney en adyuvancia y seleccionar pacientes para recibir Taxol-TTZ-PTZ x 12 sin antraciclinas en base a los resultados del ADAPT RH(-) y Her2(+)? 5. TDM1puedellegaratenerunpapelenneoadyuvancia?EncombinaciónconPTZoPTZyQt? 6. Habrá algún subgrupo de pacientes que podríamos considerar óptimas para la combinación de TDM1-Ht?

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