ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones

Transcription

1 ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones Javier Cortes, Hospital Universitario Ramon y Cajal, Madrid Vall d Hebron Institute of Oncology (VHIO), Barcelona

2 Triple Negative Breast Cancer Immunohistochemistry ER PR HER2 ER and PR <1% nuclear Histology HER2 negative : IHC 0 or 1+ staining or 2+ IHC staining with negative FISH High grade ductal

3 Poor Outcome of Metastatic TNBC (N=112) Initial therapy Time on Treatment First distant relapse 12 weeks 9 weeks 4 weeks Median D.F.I. First line chemo Second line chemo Third line chemo Kassam F, Enright K, Dent et al. Clin Breast Cancer 2009

4 What is Standard Therapy For TNBC? No specific systemic regimen guidelines exist Little data on which to base decisions Few historical controls making it challenging to design clinical trials for this subgroup

5 TNBC: Current Treatment Strategies Anthracyclines Capecitabine Biologic agents Taxanes Platinum agents TNBC paradox: chemosensitive but relapse more aggressive with worse OS Cannot treat with existing targeted therapies (hormonal therapy or trastuzumab) Manage same as other BCs with same grade & stage Limited data available from prospective trials in this population Best available data mostly subpopulation analyses

6 Martin et al, ASCO 2009 CMTN: Antraciclinas vs. Docetaxel CMTN HER2 Luminal B Docetaxel 100 mg/m 2 x 4 ciclos Doxorrubicin 75 mg/m 2 x 4 ciclos Single agent Neoadjuvant Chemotherapy study with Doxorubicin or Docetaxel for 4 cycles in Stage II-IIIa (> 3 cm) pcr rate by phenotype

7 Taxanes For Metastatic TNBC? Retrospective subgroup analyses Placebo arm data Trial Phase N Setting Taxane Outcome in TNBC CALGB III 44 First- or second-line metastatic ECOG III 110 First-line metastatic AVADO 3 III 52 First-line metastatic Paclitaxel weekly and q3w Paclitaxel weekly Docetaxel q3w ORR = 26% TTF = 2.8 months OS = 8.6 months ORR = 11.7% 4 PFS = 5.3 months ORR = 23.1% PFS = 6.1 months 1. Harris, et al. Br Cancer Res O Shaughnessy, et al. SABCS Glaspy, et al. EBCC 2010

8 Capecitabine For Metastatic TNBC? Retrospective subgroup analyses Placebo arm data Trial Phase N Setting Treatment Outcome in TNBC Pooled analysis 1 III 208 Third-line or greater metastatic Capecitabine ORR = 15% PFS = 1.7 months RIBBON-1 2 III 50 First-line metastatic Capecitabine + placebo ORR = 24% PFS = 4.2 months 1. Rugo, et al. SABCS Glaspy, et al. EBCC 2010

9 TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC Patients with ER-, PgR-/unknown, and HER2- or BRCA1/2+ metastatic or recurrent LA BC (N = 376) Carboplatin AUC6 q3w x 6 cycles (n = 188) Docetaxel 100 mg/m 2 q3w x 6 cycles ( n = 188) For both arms, crossover upon progression allowed Primary endpoint: ORR in ITT population Secondary endpoints: PFS, OS, ORR (crossover), toxicity Subgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers Tutt A, et al. SABCS 2014

10 Response at Cycle 3 or 6 (%) Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC (TNT): ORR Carboplatin Docetaxel Crossover P = % % P = % P = % 25.6% 33.3% P = % 28.1% 10 0 All Pts (n = 376) C D D C Crossover* (All pts; n = 182) BRCA1/2 Mutation (n = 43) No BRCA1/2 Mutation (n = 273) Tutt A, et al. SABCS 2014

11 Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC (TNT): Survival Survival, Mos Carboplatin Docetaxel Median PFS BRCA 1/2 mutated BRCA 1/2 not mutated Median OS Tutt A, et al. SABCS 2014

12 PFS estimate PFS estimate PFS estimate PFS estimate Bevacizumab-based Therapy: Significant Improvement in PFS E2100 (IRF assessment) 1 Bevacizumab + paclitaxel (n=368) Paclitaxel (n=354) 11.3 HR=0.48* ( ) p< Time (months) AVADO 2 Bevacizumab + docetaxel (n=247) Placebo + docetaxel (n=241) HR=0.67* ( ) p< RIBBON-1: taxane/anthracycline cohort Bevacizumab + taxane/ anthracycline (n=415) Placebo + taxane/anthracycline (n=207) HR=0.64* ( ) p< Time (months) RIBBON-1: capecitabine cohort 3 Bevacizumab + capecitabine (n=409) Placebo + capecitabine (n=206) HR=0.69* ( ) p= Time (months) Time (months) *Censored for non-protocol therapy before disease progression 15mg/kg q3w; Exploratory p-value 1. Gray, et al. JCO 2009; 2. Miles, et al. JCO Robert, et al. ASCO 2009

13 Meta-analysis:Analysis of PFS by Subgroups O Shaughnessy et al. ASCO 2010

14 Meta-analysis of First-line Bevacizumab Plus Chemotherapy in taxanes-pretreated Triple-Negative Breast Cancer Miles DW, et al. ESMO, 2010

15 Deconstructing the molecular portraits of breast cancer Basal-like Claudin-low HER2-enriched Normal-like Luminal A and B Prat & Perou Mol Oncol 2011; Prat et al. BCR 2010

16 Identification of Human TNBC Subtypes Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features Lehmann BD, et al. J Clin Invest. 2011

17 How could TNBCs be stratified? LAR BL1, BL2 IM M, MSL

18 LAR Triple negative breast cancer is comprised of 6 molecularly distinct subtypes 10% are Luminal AR (LAR) LAR express higher levels of AR mrna vs other TNBC subtypes LAR breast cancers are heavily enriched in hormonally-regulated pathways Luminal AR is more closely related to hormone receptor positive breast cancer (Luminal A and B) than to other subtypes BL= Basal Like, IM = Immunomodulatory, ML= Mesenchymal-Like, MSL= Mesenchymal Stem-like, LAR = Luminal AR

19 LAR Triple negative breast cancer is comprised of 6 molecularly distinct subtypes 10% are Luminal AR (LAR) LAR express higher levels of AR mrna vs other TNBC subtypes LAR breast cancers are heavily enriched in hormonally-regulated pathways Luminal AR is more closely related to hormone receptor positive breast cancer (Luminal A and B) than to other subtypes BL= Basal Like, IM = Immunomodulatory, ML= Mesenchymal-Like, MSL= Mesenchymal Stem-like, LAR = Luminal AR

20 LAR All LAR cell lines had some response to bicalutamide Not all of AR+ cell lines were LAR (40%) The majority (70%) of AR+ cell lines responded to bicalutamide Lehman et al CCR 2011

21 LAR LAR Cell lines All LAR cell lines had some response to bicalutamide Not all of AR+ cell lines were LAR (40%) The majority (70%) of AR+ cell lines responded to bicalutamide Lehman et al CCR 2011

22 LAR L. Denne et al, SABC 2013

23 LAR

24 LAR Traina TA, et al, SABC 2014

25 PFS (%) PFS (%) Progression-Free Survival by PREDICT AR Status ITT Population 0 1 Prior Regimens 100 n = n = PREDICT AR+ mpfs 16.0 weeks (95% CI: 10.4, 26.1) PREDICT AR+ mpfs 32.3 weeks (95% CI: 14.7, 60.3) PREDICT AR mpfs 8.0 weeks (95% CI: 7.1, 12.6) PREDICT AR mpfs 8.3 weeks (95% CI: 7.1, 15.7) Weeks Patients at risk PREDICT AR+ PREDICT AR Weeks ITT = Intent to Treat; mpfs = median progression-free survival; CI = confidence interval Cortes J, et al, ECCO 2015

26 Overall Survival (%) Overall Survival by PREDICT AR Status 100 ITT Population n = PREDICT AR+ mos 75.6 weeks (95% CI: 51.6, 91.4) PREDICT AR mos 32.3 weeks (95% CI: 20.7, 48.3) 0 Patients at risk PREDICT AR+ PREDICT AR Weeks PREDICT AR+ mos 18.0 months PREDICT AR mos 7.5 months Data cutoff 1Jul2015 ITT = intent to treat; mos = median survival; CI = confidence interval;. Cortes J, et al, ECCO 2015

27 IM Tumor cell X X T cell Anti-PDL1 X X Lung T cell Anti-PDL1 X X Akbari O, et al. Mucosal Immunol. 2010; Matsumoto K, et al. Biochem Biophys Res Commun. 2008; Chen, et al. Immunity, 2013 Dendritic cell

28 Mutational load: somatic mutations act as tumor antigens Lawrence et al, Nature 2013

29 Breast cancer has fewer mutations p<0.0001

30 Objective responses to PD-1/PD-L1 blockade in advanced TNBC Merck anti-pd1 Ab Genentech anti-pd-l1 Ab ORR 18% centrally reviewed N=32 58% PDL1+ 1% Three ORRs >1 year duration ORR 19% centrally reviewed N=21 (4 ORR +3 pseudoprogression) 23% PDL1+ IHC 2+/3+ 5%/10% Nanda 2014; Emens 2015

31 ML, MSL Eribulin Mesylate (E7389): A Novel Tubulin Targeted Agent

32 ML, MSL Eribulin Mesylate (E7389): EMT to MET phenoype Yoshida T, et al. Br J Cancer 2014

33 ML, MSL Eribulin Mesylate (E7389): EMT to MET phenoype Migration Invation Yoshida T, et al. Br J Cancer 2014

34 EMBRACE Trial: Eribulin vs TPC Overall results (n=762) Age Race Receptor status No. of organs involved Sites of disease <40 (n=51) 40 - <65 (n=560) 65 (n=151) Caucasian (n=703) Non-Caucasian (n=59) ER/PR + (n=528) ER/PR - (n=187) Unknown (n=47) ER/PR/HER2-negative (n=144) 2 (n=537) >2 (n=217) Visceral (n=624) Non-Visceral (n=130) Hazard ratio (95% CI) Favors ERIBULIN Favors TPC Based upon a stratified Cox analysis including geographic region, HER2 status, and prior capecitabine therapy as strata TPC: Treatment of Physician's Choice Cortes et al. Lancet 2011

35 Eribulin vs Capecitabine (Study 301) TN population Kaufman P, et al. JCO 2015

36 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features

37 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness)

38 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF , AACR 2012 M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features

39 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF , AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features

40 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF , AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)

41 TNBC Subtypes: (Some) Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF , AACR 2012 Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 (eribulin?) Plus PI3Ki, RAS/MEK/Erk, MET, PTEN etc, etc Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)