Secuencia óptima de tratamiento de quimioterapia en el cáncer de mama metastásico

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1 Secuencia óptima de tratamiento de quimioterapia en el cáncer de mama metastásico Javier Cortes, Ramon y Cajal University Hospital, Madrid, Spain Vall d Hebron Institute of ncology (VHI), Medica Scientia Innovation Research (MedSIR) Barcelona, Spain

2 Systemic Treatment Approach for HER2-Negative, Metastatic Breast Cancer Metastatic Breast Cancer Asymptomatic disease Limited metastases (bone & soft tissue) Positive hormone receptors Hormone responsive Disease-free interval 2 years Symptomatic disease Extensive metastases or visceral crisis Negative hormone receptors No response to hormones Hormonal Therapy Chemotherapy Response No response No progression Progression of disease If disease progresses, second-line hormonal therapy Second-line chemotherapy

3 Efficacy with different cytotoxic agents 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% VRL DCT PCT DX EPI 5-FU CAP G. Hortobagyi, ASC 2003 Educational Session

4 MBC: Systemic Treatment Approach Anthracyclines and taxanes: the standard of care Increasing use in the adjuvant setting 15-40% relapse rate after anthracycline-taxane therapy No treatment has resulted in an improvement in S after anthracyclines/taxanes Few proven options for patients failing anthracyclines/taxanes Capecitabine is the preferred agent for anthracycline and/or taxane failures Response Rates of 10-20% in phase II/III studies Limited efficacy of other agents (e.g. gemcitabine, liposomal doxorubicin, vinorelbine, )

5 US INTERN

6 RR (± 95% CI) RR Independent of Line of Therapy and Across Various Subgroups 60 P =.001 P =.029 P =.006 P =.002 P = % 42.3% 27.0% 26.5% 34.1% 33.5% % 13.2% 18.3% 18.7% 0 All First-Line Second-Line Anthracycline Visceral Patients Therapy Therapy Exposed Disease nab-paclitaxel: Solvent-based paclitaxel: Gradishar WJ, et al. J Clin ncol. 2005;23(31):

7 Probability of Survival nab-paclitaxel vs Docetaxel: Results 1.00 Investigator-Assessed Survival nab-paclitaxel 150 mg/m 2 q3w (n = 74) 33.8 months nab-paclitaxel 300 mg/m 2 q3w (n = 76) 27.7 months Docetaxel 100 mg/m 2 q3w (n = 74) 26.6 months nab-paclitaxel 100 mg/m 2 q3w (n = 76) 22.2 months Months Gradishar WJ, et al. J Clin ncol. 2011;29(Suppl 27): Abstract 275.

8 CALGB 40502: Trial Design Stratified by receipt of adjuvant taxanes and HR status Disease progression Paclitaxel 90 mg/m 2 /wk + Bevacizumab* 10 mg/kg q2w (n = 283) Treatment-naïve patients with locally recurrent or metastatic breast cancer (N = 799) nab-paclitaxel 150 mg/m 2 /wk + Bevacizumab* 10 mg/kg q2w (n = 271) Ixabepilone 16 mg/m 2 /wk + Bevacizumab* 10 mg/kg q2w (n = 245) Note: All chemotherapy given for 3 wks on, 1 wk off. *Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following DAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab. Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone. Rugo HS, et al. J Clin ncol. 2012;30(Suppl): Abstract CRA1002.

9 Proportion Progression Free 1 CALGB PFS by Treatment Arm Comparison HR P Value 95% CI Nab vs Pac Ixa vs Pac 1.53 < Paclitaxel nab-paclitaxel Ixabepilone Months Agent N Median PFS, Months from Study Entry Paclitaxel nab-paclitaxel Ixabepilone Rugo HS, et al. J Clin ncol. 2012;30(Suppl): Abstract CRA1002.

10 CALGB PFS by Treatment Arm Rugo HS, et al. J Clin ncol. 2012;30(Suppl): Abstract CRA1002.

11 Capecitabine in Anthracycline-Taxane-pretreated Metastatic Breast Cancer Study N CR + PR, % Disease Control (CR + PR + SD), % Median Response Duration, mos Median TTP, mos Median Surviva l, mos Blum et al Blum et al Reichardt et al Fumoleau et al Blum JL, et al. J Clin ncol. 1999;17: Blum JL et al. Eur J Cancer 001;37:S190 (Abstract 693) 3. Blum JL et al. Cancer 2001;92: Reichardt P et al. Ann ncol. 2003;14: Fumoleau P et al. Eur J Cancer. 2004;40:

12 Nab-paclitaxel in taxane-refractory patients Albumin-bound paclitaxel, nanoparticle formulation Phase II trial, taxane-refractory MBC (N = 106) 100 mg/m 2 weekly, Days 1, 8, and 15 every 28 days bjective PR in 16 pts (15%); PR+SD 16 wks, 32 (30%) Probability of surviving to 12 months, 38% Well tolerated without steroids or G-CSF prophylaxis Grade 4 neutropenia, 1%; grade 3, 14% Grade 3 sensory neuropathy, 4% 1. Blum JL et al., Proc Am Soc Clin ncol Abstract 543.

13 Ixabepilone

14 New Compounds Me 1 Eribulin mesylate H H 3 N Ms Me H H H H Eribulin Mesylate Etirinotecan Pegol Vinflunine

15 BEACN Phase 3 Study Design Locally recurrent or metastatic breast cancer (n=852) Prior treatment with anthracycline, a taxane, and capecitabine ECG PS prior chemotherapies for advanced disease Stable brain mets allowed R Single-Agent Etirinotecan Pegol 145 mg/m 2 every 3 weeks (n=429) Single-Agent Treatment of Physician s Choice (TPC) Docetaxel, eribulin, gemcitabine, ixabepilone, nab-paclitaxel, paclitaxel or vinorelbine Primary Endpoint verall Survival Secondary Endpoints PFS, RR, CBR, DoR, HRQoL Exploratory Endpoints PD Markers in CTC, others (n=423) Stratification: Geographic region Prior eribulin use Receptor status 135 centers in US, Canada, Belgium, France, Germany, Italy, Korea, Russia, Spain, The Netherlands, UK Enrollment: Dec 2011 Aug 2013 Event cutoff: Dec 2014 Perez E, et al. Lancet ncol 2015

16 Survival Probability Primary Efficacy Endpoint: verall Survival 1.0 Events S (95% CI) Etirinotecan Pegol (n=429) mo ( ) TPC (n=423) mo ( ) HR (95% CI): ( ) Log-rank P-value = Number at Risk: Months from Randomization Perez E, et al. Lancet ncol 2015

17 Survival Probability verall Survival in Patients With History of Brain Metastases (n=67) % ( ) 45.2% ( ) Events S (95% CI) Etirinotecan Pegol (n=36) mo ( ) TPC (n=31) mo ( ) % ( ) 19.4% ( ) HR (95% CI): ( ) Log-rank P-value = Number at Risk: Months from Randomization Perez E, et al. Lancet ncol 2015

18 VINFLUNINE: Phase III Study Design Cortes J, et al. ASC 2015

19 VINFLUNINE: S Median S Vinflunine 9.7 AA 9.3 HR 0.99 (95% CI 0.82, 1.22) p value=0.99 Cortes J, et al. Ann ncol 2018

20 Eribulin Mesylate Halichondrins a new class of antineoplastic agents Halichondria okadai H H H H H H Me Me H H H H H H Halichondrin B Me Me H H H H Me H H 3 N Ms Eribulin Mesylate 1 Me H H H H Eribulin is an synthetic analog of halichondrin B, a natural product found in marine sponges Non-taxane microtubule dynamics inhibitor Inhibits through a novel mode of action distinct from other tubulin-targeting agents Potent antiproliferative agent against many human cancer types in vitro and in vivo Active against β-tubulin mutated cell lines Unusually wide therapeutic window for a chemotherapeutic agent Eribulin induces less neuropathy in mice than paclitaxel or ixabepilone Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004; kouneva et al 2008; Smith et al 2010

21 EMBRACE Study Design Patients (n=762) Locally recurrent or metastatic breast cancer 2-5 prior chemotherapies 2 for advanced disease Prior anthracycline and taxane Progression on or within 6 months of last chemotherapy Neuropathy grade 2 ECG 2 R 2:1 Global, randomized, open-label Phase III trial (Study 305) Eribulin mesylate 1.4 mg/m 2, 2-5 min IV bolus Day 1, 8 q21 days Treatment of Physician s Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only Stratification Geographic region Prior capecitabine treatment HER2/neu status ACCRUAL: Nov 2006 Nov 2008 * Approved for treatment of cancer and administered according to local practice, if applicable. r palliative treatment or radiotherapy. Cortes J, et al. Lancet. 2011

22 % of Patients TPC Treatment Received 30% 25% 25% 96% of patients were treated with chemotherapy Total pts = % 19% 18% 15% 15% 10% 10% 10% 5% 0% n=61 n=46 n=44 n=39 n=24 n=25 n=9 4% No patients received only best supportive care or biological therapies Taxanes: paclitaxel, docetaxel, Abraxane Anthracyclines: doxorubicin, epirubicin, liposomal doxorubicin Cortes J, et al. Lancet. 2011

23 EMBRACE Updated Survival Analysis: verall Survival Treatment Eribulin (n=325) TPC (n=163) HER2, human epidermal growth factor receptor type 2; HR, hazard ratio; CI, confidence intervals; TPC, treatment of physician s choice HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata Nominal p value from stratified log-rank test. Twelves C, et al. San Antonio Breast Cancer Symposium Abstract P

24 Study Design (Study 301) Global, randomized, open-label Phase III trial (Study 301) Patients (N=1102) Locally advanced or MBC 3 prior chemotherapy regimens ( 2 for advanced disease) Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced or MBC Eribulin mesylate 1.4 mg/m 2 2- to 5-min IV Day 1 & 8 q21 days Randomization 1:1 Capecitabine 1250 mg/m 2 BID orally Days 1-14, q21 days Co-primary endpoint S and PFS Secondary endpoints Quality of life RR Duration of response 1-, 2- and 3-year survival Tumor-related symptom assessments Safety parameters Population PK (eribulin arm only) Stratification: Geographical region, HER2 status Equivalent to 1.23 mg/m 2 eribulin Kaufman P, et al. SABCS 2012

25 Survival probability verall Survival 1.0 Median S (months) Eribulin (n=554) Capecitabine (n=548) HR (95% CI 0.770, 1.003) p value = Time (months) ITT population; HR Cox model including geographic region and HER2 status as strata p value from stratified log-rank test based on clinical database Kaufman P, et al. SABCS 2012

26 Survival probability Survival probability Progression-free Survival Independent Review Median (months) Investigator Review Median (months) 1.0 Eribulin (n=554) Eribulin (n=554) Capecitabine (n=548) Capecitabine (n=548) HR (95% CI 0.932, 1.250) p value = HR (95% CI 0.857, 1.114) p value = Time (months) Time (months) ITT population; HR Cox model including geographic region and HER2 status as strata p value from stratified log-rank test based on clinical database Kaufman P, et al. SABCS 2012

27 Non-Hematologic Adverse Events Eribulin (n=544) Capecitabine (n=546) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Hand-foot syndrome < Alopecia Diarrhea <1 Nausea 22 < Vomiting 12 <1 < Fatigue <1 Asthenia 15 4 < Decreased appetite 13 < Peripheral sensory neuropathy <1 0 Pyrexia 13 <1 0 6 <1 0 Headache 13 < <1 <1 Dyspnea 10 2 < <1 Back pain <1 0 Safety population Incidence >10% (all grades) or 1% (Grade 3 or higher) in either arm; Grade 5 events also occurred in 0.7% and 0.5% of patients, respectively If a subject had two or more AEs in the same system organ class or with the same preferred term with different CTCAE grades, then the event with the highest grade was used for that subject This presentation is the intellectual property of the author.

28 Pre-Specified Subgroup Analysis Kaufman P, et al. SABCS 2012

29 Subgroup HR (95% CI) Eribulin Capecitabine Median (months) verall (0.770, 1.003) HER2 status Positive (0.688, 1.355) Negative n= (0.715, 0.983) ER status verall Survival By Receptor Status Positive (0.737, 1.093) Negative n= (0.635, 0.955) Triple negative Yes n= (0.545, 0.906) No (0.795, 1.081) ITT population Favors eribulin Favors capecitabine Kaufman P, et al. SABCS 2012

30 The Pooled Analysis Study EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician s Choice (TPC) versus Eribulin E7389) Global, open-label, randomised, pivotal Phase III trial First presented 2010 Used for the regulatory approval of Halaven in over 55 countries Study Global, open-label, randomised, two-parallelarm, pivotal Phase III trial First presented 2012 Didn t reach primary endpoint European Medicines Agency requested further evaluation Pooled analysis requested by EMA as supplementary information for review of eribulin Final decision by EMA based on two Phase III (305 and 301) trials as separate entities 1-2

31 Efficacy of eribulin in MBC by HER2 and triple negative status verall HER2 HER2+ TNR Eribulin C Eribulin C Eribulin C Eribulin C n HR 0.85 (0.77, 0.95) 0.84 (0.72, 0.93) 0.82 (0.62, 1.06) 0.74 (0.60, 0.92) (95% CI) a p

32 Eribulin s Mechanisms of Action 1. Tubulin-based Antimitotic Effects 2. Complex Non-Mitotic Effects on Tumor Biology* 1. Tumor Vasculature Remodeling 2. Reversal of EMT 3. Decrease Capacity for Migration and Invasion *As shown in preclinical studies

33 Eribulin blocks mitotic spindle formation, causing cell death by apoptosis Towle MJ, et al. Cancer Res 2001; Kuznetsov G, et al. Cancer Res 2004

34 After a single dose of Eribulin, Perfusion becomes uniform across tumor core and rim Funahashi Y, et al. Cancer Sci 2014

35 Eribulin induces epithelial morphology in surviving breast cancer cells in vitro Yoshida T, et al. Br J Cancer 2014

36 Eribulin reverses EMT in Tumors in vivo Yoshida T, et al. Br J Cancer 2014

37 Eribulin decreases in vitro migration and invasion Yoshida T, et al. Br J Cancer 2014

38 Experimental metastases in mice

39 Eribulin prevents experimental metastasis and increases survival in mice Yoshida T, et al. Br J Cancer 2014

40 Eribulin Mesylate: ngoing Clinical Trial Programme NeoEribulin: A Phase II, open-label, single-arm, pharmacogenomic study of single agent E7389 (eribulin mesylate) as neoadjuvant treatment for operable Stage I-IIIA HER2 non-overexpressing breast cancer Pharmacogenomic Study of Eribulin in HER2-ve BC -EISAI Phase II, open-label, single-arm exploratory study of the safety and pharmacogenomics of single agent E7389 (eribulin mesylate) in patients with operable Stage I-IIIA HER2 non-overexpressing breast cancer (J. Cortés) N 200 S I and IIIA perable HER2 Negative Core or Incisional Biopsy Imaging Dx Gene Expression Profile Day 21 Core Biopsy PE Mammo/US/MRI ERIBULIN 1.4 mg/m 2 D1, D8 Q21days 4 Cycles Eribulin Safety RR BRR U R G E R Y pcr B pcr BL BCR > 60% Post-Surgery Treatment as per Investigator (Anthracylinebased therapy recommended) DFS C N F I D E N T I A L

41 Eribulin Mesylate: ngoing Clinical Trial Programme Prat A, et al. SABCS 2015

42 Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to Tumor Subtype and Line of Therapy Number of lines of chemotherapy by line and subtype Median duration of chemotherapy according to line and subtype Seah DSE et al. J Natl Compr Canc Netw 2014

43 CASCADE STUDY: Patient Prevalence decay per line of treatment and tumour immunotype

44 Chemo-based Treatment Approach for HER2- Negative, Metastatic Breast Cancer Metastatic Breast Cancer Scientific approach Anthracyclines and taxanes pretreated Regulatory approach Anthracyclines and taxanes pretreated Eribulin (TNMBC) (HER2 neg?) /IF capecitabine decided) Capecitabine Gemcitabine Vinorelbine Progression of disease (after 1 lines) If disease progresses, Second/third-line chemo therapy Eribulin