Novedades en tratamiento con quimioterapia en Cáncer de Mama. Dr E Ciruelos S Oncología Médica Hospital 12 de Octubre, Madrid

Transcripción

1 Novedades en tratamiento con quimioterapia en Cáncer de Mama Dr E Ciruelos S Oncología Médica Hospital 12 de Octubre, Madrid

2 Evolución de la quimioterapia en cáncer de mama avanzado Mid 20 th century Late 20 th century Late 20 th century Early 21 st century Early chemotherapy CMF (VP) Anthracyclines Vinorelbine Taxanes Capecitabine Biological era begins Novel antitubulins Advanced cytotoxics CMF = cyclophosphamide + methotrexate + 5-flourouracil; VP = vincristine + prednisone

3 A quién tratar con QT?

4 Factores que determinan la elección del tratamiento en el cáncer de mama avanzado Características de la enfermedad Carga de enfermedad Respuesta a terapias previas Agresividad de la enfermedad Estatus de RH (ER y PgR) y HER2 Intervalo libre de enfermedad Terapia adyuvante previa Elección del tratamiento Disponibilidad Coste del tratamiento Guías y recomendaciones Características de la paciente Preferencia de la paciente (oral vs IV), toxicidades Aspectos socioeconómicos y psicológicos (ej.: distancia desde la casa y el hospital, costes) Edad, PS, comorbilidades Estado menopáusico: SI vs. NO ABC2 Guidelines, Ann Oncol 2014

5 ALGORITMO DE TRATAMIENTO Paciente postmenopáusica* con cancer de mama avanzado RH+ y HER2- Continuar con la terapia hormonal hasta progresión o toxicidad inaceptable Progresión Sin beneficio clínico luego de varios regímenes consecutivos de terapia hormonal O Enfermedad visceral sintomática Sí No Quimioterapia EECC con una nueva terapia hormonal

6 Cáncer de mama TN: Subtipos intrínsecos Prat A. The Oncologist 2013

7 Nuevas formulaciones: Nuevos fármacos

8 Nuevas formulaciones: Nuevos fármacos Nab-Paclitaxel

9 QT clásica: Nuevas formulaciones

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11 Cáncer de mama metastásico: Nanotecnología Abraxane PFS, months 300 mg/m 2 q3w N Arm A (n = 76) Media n nab-paclitaxel 100 mg/m 2 N qw 3/4 Arm B (n = 76) Media n 150 mg/m 2 qw 3/4 Arm C (n = 74) Docetaxel 100 mg/m 2 q3w Arm D (n = 74) N Median N Median Overall P value a All patients < 65 years 65 years DM Visceral Nonvisceral Lesion sites < 5 5 Premenopausal Postmenopausal a Based on log-rank test DM, dominant metastasis; PFS, progression-free survival; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks > Gradishar W. et al. ECCO [Abstract 5060].

12 GeparSepto: Phase III Neoadjuvant Trial of nab-p vs sb-p Regimens in Early Breast Cancer Final Study Design (after 400 patients) 12 HER, human epidermal growth factor receptor; HR, hormone receptor; nab-p, nab-paclitaxel; sb-p, solvent-based paclitaxel. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer GBG 69 GeparSepto. Oral presented at: San Antonio Breast Cancer Symposium December 9-13, 2014; San Antonio, Texas. [oral S2-07].

13 GeparSepto: Phase III Neoadjuvant Trial of nab-p vs sb-p Regimens in Early Breast Cancer Primary Endpoint (pcr: ypt0 ypn0) 13 nab-p, nab-paclitaxel; pcr, pathological complete response; sb-p, solvent-based paclitaxel. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer GBG 69 GeparSepto. Oral presented at: San Antonio Breast Cancer Symposium December 9-13, 2014; San Antonio, Texas. [oral S2-07].

14 GeparSepto: Phase III Neoadjuvant Trial of nab-p vs sb-p Regimens in Early Breast Cancer Secondary Endpoints: pcr Rates According to Other Definitions 14 nab-p, nab-paclitaxel; pcr, pathological complete response; sb-p, solvent-based paclitaxel. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer GBG 69 GeparSepto. Oral presented at: San Antonio Breast Cancer Symposium December 9-13, 2014; San Antonio, Texas. [oral S2-07].

15 GeparSepto: Phase III Neoadjuvant Trial of nab-p vs sb-p Regimens in Early Breast Cancer pcr in Stratified Subgroups 15 Parameter Subgroup pcr, % P Value SPARC SPARC SPARC+ Ki67 Ki67 20% Ki67 >20% 28.8 vs vs vs vs Biological subtype HER2, HR+ HER2, HR HER2+, HR+ HER2+, HR 12.0 vs vs vs vs < HER2 HER2 HER vs vs 61.8 < HR status HR HR vs vs 29.9 < HER, human epidermal growth factor receptor; HR, hormone receptor; nab-p, nab-paclitaxel; pcr, pathological complete response; sb-p, solvent-based paclitaxel; SPARC, secreted protein acidic and rich in cysteine. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer GBG 69 GeparSepto. Oral presented at: San Antonio Breast Cancer Symposium December 9-13, 2014; San Antonio, Texas. [oral S2-07].

16 Nuevas formulaciones: Nuevos fármacos Etirinotecan

17 Etirinotecan (NKTR 102) Pegilado en polímero (prodroga inactiva) Se libera en capilares de microvasculatura tumoral Hidrólisis a droga activa Inhibición de síntesis de DNA No pico plasmático

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20 Etirinotecan: Fase II en CMM NKTR mg/m 2 q14 days ORR, RECIST v 1.0 n/n (%) Evaluable Patients NKTR mg/m 2 q21 days TOTAL Prior A/T 7/22 (32%) 5/21 (24%) 12/43 (28%) Triple Negative 2/8 (25%) 5/10 (50%) 7/18 (39%) Prior A/T/C 2/6 (33%) 3/10 (30%) 5/16 (31%) Median PFS (m) Median OS (m) Awada A, et al. IMPAKT 2012

21 Etirinotecan: Estudio BEACON N=840 CMM o localmente recurrente 2-5 líneas previas QT 2 líneas en CMM Previo A, T y Cape R 1:1 NKTR mg/m 2 /21d Tratamiento a elección (TPC) * Monoterapia (eribulina, ixabepilona, vinorelbina, gemcitabina, taxanos) PI: J. Cortés Estratificación Area geográfica Eribulina previa Subtipo histológico * Eribulina 40%, VNR 23%, gemcitabina 18%, taxano 15%, ixabepilona 4%

22 Etirinotecan: Estudio BEACON Median OS 12.4 vs 10.3 months (HR 0.87; p 0.08) Brain mets (67 pts): mos 10 vs 4.8 m (HR 0.51; p<0.01) Liver mets (456 pts): mos 10.9 vs 8.3 m (HR 0.73; p 0.002) Grade > 3 AEs: 48 vs 63% Perez EA, ASCO June 2015

23 Antimicrotúbulos no taxanos Eribulina

24 Eribulin s novel mechanism of inhibiting microtubule dynamics (Jordan et al., 2005) Eribulin 1 Eribulin inhibits microtubule growth Microtubule Dynamics Growing microtubule Microtubule Polymerization 3 Eribulin causes globular tubulin aggregates Eribulin MTOC Shortening microtubule 2 Microtubule Depolymerization Eribulin has no effect on microtubule shortening Globular tubulin aggregates MT drawing created by M. Asada, TRL, Eisai; later adapted by B. Littlefield, ERI

25 Phase II studies confirmed activity of eribulin in patients with pre-treated MBC 201 Study 1 (N=103): Prior taxane & anthracycline* 211 Study 2 (N=299): Prior taxane, anthracycline, & capecitabine* Primary endpoint: ORR with independent review Secondary endpoints: DOR, PFS, OS, AEs ORR: 11.5% Median DOR: 5.6 months Median PFS: 2.6 months 6-month PFS 25.9% (95% CI, 15.5, 36.3) Median OS: 9.0 months (range months) 6-month survival 67.8% (95% CI, 58.0, 77.6) 1-year survival 45.7% (95% CI, 35.2, 56.2) ORR: 9.3% Median DOR: 4.1 months Median PFS: 2.6 months 6-month PFS 15.6% (95% CI, 10.7, 20.5) Median OS: 10.4 months 6-month survival 72.3% (95% CI, 66.9, 77.6) *MBC patients with progression of disease 6 months of last chemotherapy and, if present, pre-existing neuropathy grade 2 AEs = adverse events; CI = confidence interval; DOR = duration of response; MBC = metastatic breast cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival 1. Vahdat L, Pruitt B et al. J Clin Oncol. 2009;27: ; 2. Cortes J, Vahdat L et al. J Clin Oncol. 2010;28:

26 Halaven has been evaluated in two of the largest, Phase 3 randomised trials conducted in MBC 1,2 EMBRACE study 1 (N=762) Study (N=1102) La indicación en segunda línea en la que se administró el fármaco a los s pacientes en el estudio 301 no está financiada por el sistema nacional de salud. 2 prior regimens for advanced disease Median of four prior chemotherapy regimens HER2-negative 74%; TNBC 19% Comparator: single TPC Primary endpoint: OS Secondary endpoints: PFS, ORR, DOR 2 prior regimens for advanced disease 3 prior chemotherapy regimens 1 prior chemotherapy: 573 patients All prior anthracycline/taxane (25/46% refractory) HER2-negative 68.5%; TNBC 26.0% Comparator: capecitabine Co-primary endpoints: OS and PFS Secondary endpoints: ORR, survival at 1, 2 and 3 years, QoL DOR, duration of response; ORR, objective response rate; QoL, quality of life; TPC, treatment of physician s choice. In EMBRACE study, TPC was defined as any single-agent chemotherapy, hormonal therapy or targeted therapy approved for the treatment of cancer, radiotherapy, or best supportive care. TPC was selected prior to randomisation to eliminate any bias Cortes J, et al. Lancet. 2011;377: ; 2. Kaufman PA, et al. J Clin Oncol. 20 Feb 2015.

27 Halaven has been evaluated in two of the largest, Phase 3 randomised trials conducted in MBC 1,2 EMBRACE study 1 (N=762) Study (N=1102) La indicación en segunda línea en la que se administró el fármaco a los s pacientes en el estudio 301 no está financiada por el sistema nacional de salud. 2 prior regimens for advanced disease Median of four prior chemotherapy regimens HER2-negative 74%; TNBC 19% Comparator: single TPC Primary endpoint: OS Secondary endpoints: PFS, ORR, DOR 2 prior regimens for advanced disease 3 prior chemotherapy regimens 1 prior chemotherapy: 573 patients All prior anthracycline/taxane (25/46% refractory) HER2-negative 68.5%; TNBC 26.0% Comparator: capecitabine Co-primary endpoints: OS and PFS Secondary endpoints: ORR, survival at 1, 2 and 3 years, QoL DOR, duration of response; ORR, objective response rate; QoL, quality of life; TPC, treatment of physician s choice. In EMBRACE study, TPC was defined as any single-agent chemotherapy, hormonal therapy or targeted therapy approved for the treatment of cancer, radiotherapy, or best supportive care. TPC was selected prior to randomisation to eliminate any bias Cortes J, et al. Lancet. 2011;377: ; 2. Kaufman PA, et al. J Clin Oncol [Epub ahead of print].

28 EMBRACE: Updated OS analysis Median OS, months Eribulin (n=508) 13.2 TPC (n=254) 10.5 HR % CI 0.67, 0.96 P value* Analysis occurred at 589 events (deaths), representing 77% of the ITT population *Nominal P value from stratified log-rank test CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; OS = overall survival; TPC = treatment of physician s choice Cortes J, O Shaughnessy J et al. Lancet. 2011;377: ; Twelves C, Loesch D et al. San Antonio Breast Cancer Symposium. 2010;Poster P

29 Halaven has been evaluated in two of the largest, Phase 3 randomised trials conducted in MBC 1,2 EMBRACE study 1 (N=762) Study (N=1102) La indicación en segunda línea en la que se administró el fármaco a los s pacientes en el estudio 301 no está financiada por el sistema nacional de salud. 2 prior regimens for advanced disease Median of four prior chemotherapy regimens HER2-negative 74%; TNBC 19% Comparator: single TPC Primary endpoint: OS Secondary endpoints: PFS, ORR, DOR 2 prior regimens for advanced disease 3 prior chemotherapy regimens 1 prior chemotherapy: 573 patients All prior anthracycline/taxane (25/46% refractory) HER2-negative 68.5%; TNBC 26.0% Comparator: capecitabine Co-primary endpoints: OS and PFS Secondary endpoints: ORR, survival at 1, 2 and 3 years, QoL DOR, duration of response; ORR, objective response rate; QoL, quality of life; TPC, treatment of physician s choice. In EMBRACE study, TPC was defined as any single-agent chemotherapy, hormonal therapy or targeted therapy approved for the treatment of cancer, radiotherapy, or best supportive care. TPC was selected prior to randomisation to eliminate any bias Cortes J, et al. Lancet. 2011;377: ; 2. Kaufman PA, et al. J Clin Oncol. 20 Feb 2015.

30 Proportion of survival Study 301: A trend toward improved overall survival with eribulin vs capecitabine (ITT population) Study 301 Median OS (co-primary endpoint) vs capecitabine showed a numerical difference in favour of Halaven, but was not statistically significant Median OS (months) Eribulin (n=554) 15.9 Capecitabine (n=548) 14.5 HR % CI 0.770, P value* There was no difference in PFS between the 2 treatment arms Number of subjects at risk Time (months) *Stratified log-rank test based on geographical region and HER2 status. One-, 2-, and 3-year survival rates were 64.4% and 58.0% (P=0.04), 32.8% and 29.8% (P=0.32), and 17.8% and 14.5% (P=0.18) for eribulin and capecitabine, respectively. Halaven Summary of Product Characteristics. Kaufman PA, et al. J Clin Oncol [Epub ahead of print]

31 Breast Cancer Res Treat. Sep 2014 DOI /s y CLINICAL TRIAL Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies Chris Twelves Javier Cortes Linda Vahdat Martin Olivo Yi He Peter A. Kaufman Ahmad Awada

32 Proportion of survival Overall survival in the ITT population: Median OS (months) Eribulin (n=1062) 15.2 Control (n=802) 12.8 HR % CI 0.768, P value months difference Number of subjects at risk Time (months) Data on file ERI-104 Hazard ratio stratified by region, HER2 status, prior capecitabine use and study Overall survival curves adjusted by study 305 study data is updated 77% event analysis

33 Event/N Overall survival in HER2 subgroups Median OS (months) Subgroup Eribulin Control HR (95% CI) P value Eribulin Control Overall 832/ / (0.768, 0.948) HER2 status Positive 139/ / (0.624, 1.063) Negative 581/ / (0.743, 0.952) Negative* 581/ / (0.722, 0.929) TNBC patients Yes 201/ / (0.599, 0.917) No 543/ / (0.757, 0.981) Favours eribulin Favours control * Additionally stratified by triple-negative status

34 Toxicidad Estudio 301 Estudio 305 Toxicidad G3/4 Eribulina Capecitabina Eribulina Control HEMATOLOGICA Anemia 2% 1% 2-3% 4% Neutropenia 46% 5% 45% 21% Neutropenia febril 2% 1% 4% 1% Trombopenia 0.5% 1% NO HEMATOLOGICA Astenia/Fatiga 6% 6% 9% 10% Neuropatía sensitiva 3.5% 0.5% 9% 2% Alopecia 35% 4% 45% 10% Naúseas 0.2% 1.6% 1% 2% Sd Mano-pie 0% 14.5% Diarrea 1.1% 5.3%

35 Eribulin: New approved clinical indication in EU (*) HALAVEN monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two one chemotherapeutic regimen for advanced disease (see section 5.1). Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments (*) SmPC approved by EMA in June 2014.

36 Platinos: Nuevos datos clínicos

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46 Antiangiogénicos: Nuevos datos clínicos

47 Bevacizumab en 1ª línea CMM

48 Bevacizumab en 1ª línea CMM

49 Bevacizumab en 1ª línea CMM

50 IMELDA: Open-label randomised phase III trial 3 6 cycles Previously untreated HER2-negative LR/mBC BEV 15 mg/kg + DOC mg/m 2 d1 q3w CR, PR or SD Stratification factors ER status (positive vs negative) Visceral metastasis (present vs absent) Stable disease/response/non-measurable disease LDH concentration ( 1.5 vs >1.5 ULN) R 1:1 BEV 15 mg/kg d1 q3w BEV 15 mg/kg d1 + CAP 1000 mg/m 2 bid d1 14 q3w Treat to PD, unacceptable toxicity or withdrawal of consent CAP = capecitabine; CR = complete response; ER = oestrogen receptor; LDH = lactate dehydrogenase; PR = partial response; SD = stable disease; R = randomisation; ULN = upper limit of normal.

51 Withdrawn before treatment (N=3) Patient disposition Enrolled (N=287) Discontinued initial treatment (N=99) PD (N=41) AE/toxicity (N=31) Other reason (N=27) a a Withdrew consent/patient s decision (N=13), inclusion/exclusion criteria or protocol violation (N=5), investigator/medical decision (N=4), health authority/study termination (N=3), death (N=2) Treated in initial phase (N=284) Completed initial treatment and randomised (N=185) R AE = adverse event BEV alone (N=94) Treated (N=92) Untreated (N=2) BEV CAP (N=91) Treated (N=91)

52 Estimated probability Primary endpoint: PFS from time of randomisation BEV (N=94) BEV CAP (N=91) Events, n (%) 83 (88) 69 (76) Median PFS, months (95% CI) Stratified hazard ratio (95% CI) Stratified 2-sided log-rank test 4.3 ( ) 0.38 ( ) p< ( ) Time from randomisation (months) No. at risk BEV CAP BEV

53 PFS in prespecified subgroups Subgroup No. of events/patients (%) Median PFS, months Unstratified hazard ratio (95% CI) BEV CAP BEV BEV CAP BEV Favours BEV CAP Favours BEV All (stratified) 69/91 (76) 83/94 (88) Age <65 years 57/77 (74) 73/81 (90) Age 65 years 12/14 (86) 10/13 (77) Triple negative 19/25 (76) 21/21 (100) Hormone receptor positive 50/66 (76) 62/73 (85) ER positive a 48/64 (75) 59/69 (86) ER negative a 21/27 (78) 24/25 (96) <3 metastatic organ sites 39/48 (81) 33/40 (83) metastatic organ sites 30/43 (70) 50/54 (93) Visceral metastases a 47/62 (76) 60/65 (92) No visceral metastases a 22/29 (76) 23/29 (79) Response a 53/68 (78) 59/68 (87) Stable disease a 13/20 (65) 21/22 (95) LDH 1.5 ULN a 64/85 (75) 78/89 (88) LDH >1.5 ULN a 5/6 (83) 5/5 (100) a Stratification factors (data at randomisation)

54 Estimated probability IMELDA: OS from time of randomisation BEV (N=94) BEV CAP (N=91) Events, n (%) 53 (56) 33 (36) 1-year OS rate (%) year OS rate (%) Stratified hazard ratio (95% CI) Stratified 2-sided log-rank 0.43 ( ) p< Median, months (95% CI) ( ) (32.3 NR) (95% CI: ) 39.0 (95% CI 32.3 NR) Time from randomisation (months) No. at risk BEV CAP

55 Bevacizumab: biomarcadores predictivos

56 Miles D, ASCO 2013

57 Conclusiones Nuevas formulaciones: nab-placitaxel - significativamente mejor que paclitaxel en neoadyuvancia

58 Conclusiones Nuevas formulaciones: nab-placitaxel - significativamente mejor que paclitaxel en neoadyuvancia Nuevas formulaciones: Etirinotecan - significativamente mejor que irinotecan en algunos subgrupos

59 Conclusiones Nuevas formulaciones: nab-placitaxel - significativamente mejor que paclitaxel en neoadyuvancia Nuevas formulaciones: Etirinotecan - significativamente mejor que irinotecan en algunos subgrupos Nuevos antimicrotúbulos: Eribulina - tras antraciclinas y taxanos como alternativa a capecitabina

60 Conclusiones Platinos - en fenotipo triple negativo, fundamentalmente en basal like y BRCA mutado (línea germinal)

61 Conclusiones Platinos - en fenotipo triple negativo, fundamentalmente en basal like y BRCA mutado (línea germinal) Bevacizumab - en esquema de mantenimiento con capecitabina en pacientes respondedores a 1ª línea con taxano

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