Current and Future Perspectives in Treatment of Metastatic Triple Negative Breast Cancer (TNBC) Yeon Hee Park M.D., Ph.D.

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1 Current and Future Perspectives in Treatment of Metastatic Triple Negative Breast Cancer (TNBC) Yeon Hee Park M.D., Ph.D. Breast Cancer Center, Medical Oncology Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea

2 Chemotherapy Overview Antiangiogenic Therapy Heterogeneity of TNBCs Future Perspectives in TNBCs

4 Guidelines First-line therapy Second- or later-line therapy ESMO 1 Individualised CT (taxane, level 1) CT (there is no standard regimen) CECOG 2 CT (no optimal regimen defined) a Non-Ac/non-taxane-based CT (after Ac and taxane failure) a NCCN 3 Canada 4 CT (using preferred single agents or combinations) CT (Ac or taxane [± capecitabine or gemcitabine]) a CT (using preferred single agents or combinations) CT (capecitabine, taxane [± capecitabine or gemcitabine], vinorelbine) a France 5 CT (taxane-based combination) a No specific recommendation Germany (AGO b ) 6 CT as for HER2 MBC (AGO++) CT as for HER2 MBC (AGO++) Italy (AIOM) 7 Individualised CT a No specific recommendation Spain (SEOM) 8 Individualised CT a Non-Ac/non-taxane-based CT (after Ac and taxane failure) a a General guideline for mbc; no specific recommendations provided for locally recurrent/metastatic TNBC; b AGO level of evidence: ++ use supported in selected situations; + use supported, however, low level of evidence; +/- data do not support routine use AGO = Arbeitsgemeinschaft Gynäkologische Onkologie; AIOM = Associazione Italiana di Oncologia Medica; CECOG = Central European Oncology Group; CT = chemotherapy; ESMO = European Society for Medical Oncology; NCCN = National Comprehensive Cancer Network; SEOM = Spanish Medical Oncology Society; 1. Cardoso et al. Ann Oncol 2010; 2. Beslija et al. Ann Oncol 2009; 3. NCCN 2015; 4. Cancer Care Ontario; 5. RPC Nice Saint Paul de Vence 2009 Oncologie 2009; 6. AGO 2010; 7. AIOM 2011; 8. Alvarez López et al. Clin Transl Oncol 2010

ESMO Clinical Practice Guidelines: Selection of Available Chemotherapy Agents and Regimens for MBC Taxane containing Paclitaxel monotherapy weekly Docetaxel monotherapy 3-weekly or weekly

5 ESMO Clinical Practice Guidelines: Selection of Available Chemotherapy Agents and Regimens for MBC Taxane containing Paclitaxel monotherapy weekly Docetaxel monotherapy 3-weekly or weekly Doxorubicin/taxane (paclitaxel or docetaxel) Epirubicin/taxane (paclitaxel or docetaxel) Docetaxel/capecitabine Paclitaxel/gemcitabine Paclitaxel/vinorelbine Paclitaxel/carboplatin Non-anthracycline containing Cyclophosphamide/methotrexate/5-fluorouracil (CMF) Platinum-based combinations Capecitabine Vinorelbine Gemcitabine Capecitabine+ vinorelbine Vinorelbine ± gemcitabine Oral cyclophosphamide ± methotrexate (metronomic) Anthracycline containing Doxorubicin or epirubicin monotherapy (weekly or 3 weekly) Doxorubicin or epirubicin/cyclophosphamide Liposomal doxorubicin ± cyclophosphamide 5-FU/doxorubicin/cyclophosphamide (FAC) 5-FU/epirubicin/cyclophosphamide (FEC) New cytotoxic agents Ixabepilone Nab-paclitaxel 5-FU = 5-fluorouracil; Nab = nanoparticle albumin bound; RCT = randomised controlled trial 1. Cardoso et al. Ann Oncol 2010

06) However. OS HR (95% CI) Meta-analysis of 3 first-line studies of chemo ± bevacizumab 0.96 (0.79-1.

8 Bevacizumab in TNBC: Stage IV Setting First-line randomized phase III trials: Stage IV Trial Regimen DFS HR (95% CI) ECOG-E2100 Weekly paclitaxel + bevacizumab 0.53 ( ) AVADO Docetaxel + bevacizumab 0.68 (NR~1.00) RIBBON-1 Chemotherapy + bevacizumab 0.72 ( ) However. OS HR (95% CI) Meta-analysis of 3 first-line studies of chemo ± bevacizumab 0.96 ( ) RIBBON-2 randomized phase III trial, pretreated: TNBC subset HR (95% CI) chemo + bevacizumab PFS ( ) * exploratory OS ( ) O Shaughnessy J et al, ASCO 2011; Brufsky BCRT 2012

Bevacizumab and Response in HER2-Negative Breast Cancer Trial Regimen RR Bev arm RR placebo Initial Ph 3 Capecitabine ± B 20%* 9% E2100 Paclitaxel ± B 37%* 21% AVADO Docetaxel ± B 64%* 46% RIBBON-1

9 Bevacizumab and Response in HER2-Negative Breast Cancer Trial Regimen RR Bev arm RR placebo Initial Ph 3 Capecitabine ± B 20%* 9% E2100 Paclitaxel ± B 37%* 21% AVADO Docetaxel ± B 64%* 46% RIBBON-1 Chemotherapy ± B 35%* 24% RIBBON-2 (TNB C subset) Chemotherapy ± B 41%* 18% *statistically significant Miller et al, JCO 05; Miller et al, NEJM 07; Miles et al, JCO 10; Robert et al, JCO 11 Brufsky et al, BCRT 12

10 Months Clinical benefit shown in randomised controlled trials PFS PFS TTP PFS PFS 10.6 Replicated in phase II studies CT Bevacizumab + CT PFS E RIBBON-1 ATHENA 3,a Brufsky 4 German Japanese (capecitabine) 2 Study 5 Study 6 a Patients treated with taxane alone or in combination, according to clinician s choice, or alternative chemotherapy (monotherapy or doublet, excluding anthracycline) if taxane not considered standard of care. Bevacizumab is not indicated for use in combination with docetaxel. 1. O Shaughnessy et al. SABCS 2009; 2. Glaspy et al. EBCC 2010; 3. Pritchard et al. SABCS 2010; 4. Brufsky et al. Clin Breast Cancer 2011; 5. Schneeweiss et al. EMCC2011; 6. Aogi et al. Breast Cancer Res Treat 2011

VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGFR2 VEGF-A Ramucirumab Endothelial cell VEGFR2 VEGF-A VEGF-C VEGF-D Ramucirumab binds to

11 VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGFR2 VEGF-A Ramucirumab Endothelial cell VEGFR2 VEGF-A VEGF-C VEGF-D Ramucirumab binds to VEGFR2, blocks VEGF ligand binding Ligand binding activates VEGFR2 and p44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vessel formation and tumor growth

12 ROSE RANDOMIZATION 2:1 N=1,144 Docetaxel 75mg/m² I.V. q3wks Blinded Ram 10mg/kg I.V. q3wks Docetaxel 75mg/m² I.V. q3wks Progressive Disease Or Unacceptable Toxicity Or Consent Withdraw Follow-up for PD and for OS Blinded Placebo I.V. q3wks JCO 33; , 2014

13 Antiangiogenic Therapy in TNBC Bevacizumab has unusual activity profile Augments PFS but has zero impact on OS Augments response added to chemotherapy Where response is the endpoint, adding bevacizumab (where available) is an option (as is polychemotherapy) The benefit of bevacizumab is achieved with limited impact on the tolerability of chemotherapy Antiangiogenic strategies outside of bevacizumab are a work in progress. Selection strategies remain the challenge

14 Significant Clinical Implications

15 Molecular Subtypes and IHC Profile Carey, L. A. et al. JAMA 2006;295:

16 Slide 16 TNBC, BLBC and BRCA By Default! TNBC BRCA1 BLBC BRCAness DNA repair defect Treatment strategies for BRCA1-deficient cancers may be relevant for sporadic triple negative disease, X chromosome inactivation TP53 mutation Genomic instability TNBC classification significantly enriches for BLBC (~75%), however, it misses ~25% of BLBC and includes ~25% of tumors that are non-blbc. A Free sample background from

17 Slide 17 Rational treatment by Biology 2003 By Default! Basal Basoluminal Luminal ER positive ER negative Weigelt, B. et al. Cancer Res 2005;65: A Free sample background from Nat Clin Pract Oncol 4(9): , 2007

18 Slide 18 Poly(ADP-ribose) polymerase (PARP) 2003 By Default! PARP (active) PARP (inactive) A key regulator of DNA damage repair processes Involved in DNA base-excision repair (BER) Binds directly to DNA damage Produces large branched chains of poly (ADP-ribose) Attracts and assists BER effectors Virág L and Szabó S, Pharmacol Rev 2002;54: A Free sample background from

19 Slide 19 PARP1, BRCA1, and DNA repair 2003 By Default! BRCA deficiency Platinum agents Synthetic lethality PARP-1 inhibitor A Free sample background from Cancer Sci 98: , 2007

Gem/Cis +/- BSI-201 Metastatic TNBC with prior

6 mg/kg d 1, 4, 8, 11 q 3W PFS 6.9 vs 3.

22 Gem/Cis +/- BSI-201 Metastatic TNBC with prior palliative chemotherapy (n=120) R Gemcitabine 1000 mg/m2 d 1, 8 Carbo AUC 2 d 1, 8 q 3W Gemcitabine 1000 mg/m2 d 1, 8 Carbo AUC 2 d 1, 8 BSI mg/kg d 1, 4, 8, 11 q 3W PFS 6.9 vs 3.3 months P < , HR = O Shaugnessy et al ASCO abstract #3 NEJM, 2011: 364;

drug developer has decided to conduct molecular analysis

23 After a failed phase III trial of Sanofi-Aventis triple-negative breast cancer candidate iniparib, the drug developer has decided to conduct molecular analysis to try to identify best responders to the drug. Genomeweb.com

24 The relationship between BRCA1 and TNBCs and issues in selection of target population Do sporadic tumors with reduced BRCA1 expression behave in the same way as BRCA1-mutatnt tumors? Maybe not,

25 Reasons for PARPi Failure for TNBC Heterogeneity of TNBCs No Companion Diagnostics, No biomarker Myriad gene patent litigation

28 Platinum Presented By Melinda Telli at 2014 ASCO Annual Meeting

29 Non-BRCA1 TNBC and Platinums in MBC Stage IV Trials Population Results Control arm BALI-1 (Cisplatin) Sporadic TNBC 10% RR Control arm Phase III iniparib (Gem/carbo) Sporadic TNBC 30% RR TBCRC 001 (Cetuximab/Carbo) Sporadic TNBC 17% RR TBCRC009 (Carboplatin or Cisplatin) Sporadic TNBC 30% RR Platinum agents and DNA-damaging chemotherapy: Active Whether more active than another drug not known We need a selection strategy Baselga, ESMO 10; O Shaughnessy, ASCO 11; Carey et al, JCO 12; Isakoff, ASCO 11

30 Slide 28 Presented By Melinda Telli at 2014 ASCO Annual Meeting

Response at Cycle 3 or 6 (%) 90 80 70 60 50 40 30 20 10 0 31.4% P =.44 35.6% All Pts (n = 376) Tutt A, et al. SABCS 2014. Abstract S3-01. Carboplatin Docetaxel Crossover P =.73 22.8% 25.

31 Response at Cycle 3 or 6 (%) % P = % All Pts (n = 376) Tutt A, et al. SABCS Abstract S3-01. Carboplatin Docetaxel Crossover P = % 25.6% C D D C Crossover* (All pts; n = 182) P = % 33.3% BRCA1/2 Mutation (n = 43) 28.1% P = % No BRCA1/2 Mutation (n = 273) *Excludes those with no first progression or not starting crossover treatment.

32 Progression free survival, % Months from randomization Tutt A, et al. SABCS Abstract S Carboplatin + BRCA1/2 mutated Carboplatin + BRCA1/2 not mutated Docetaxel + BRCA1/2 mutated Docetaxel + BRCA1/2 not mutated Median PFS, mos Carbo Doc BRCA1/2 mutated BRCA1/2 not mutated

33 Old drugs, new tricks for TNBC PFS OS

34 Despite inclusion in some guidelines, the clinical benefit of platinum therapy in TNBC relative to other subtypes remains controversial Potential for synergy reported between platinum and gemcitabine, anti-egfr therapy, and PARP inhibitors Identify target population

35 Identification of Biomarkers to Predict Response to Single-Agent Platinum Chemotherapy in Metastatic Triple Negative Breast Cancer (mtnbc): Correlative studies from TBCRC009 Presented By Steven Isakoff at 2014 ASCO Annual Meeting

36 Homologous Recombination Presented By Christine Walsh at 2014 ASCO Annual Meeting

37 TBCRC009: Study Design Presented By Steven Isakoff at 2014 ASCO Annual Meeting

38 N=86 Efficacy: <br />Response by BRCA1/2 Status Presented By Steven Isakoff at 2014 ASCO Annual Meeting

39 BRCA1/2 germline mutation does not predict longer PFS or OS Presented By Steven Isakoff at 2014 ASCO Annual Meeting

40 Homologous Recombination Deficiency (HRD) Assays Presented By Steven Isakoff at 2014 ASCO Annual Meeting

41 Platinum sensitivity is associated with higher HRD scores Presented By Steven Isakoff at 2014 ASCO Annual Meeting

42 Conclusions: <br />Homologous Recombination (HR) Presented By Christine Walsh at 2014 ASCO Annual Meeting

43 Genomic Chaos: TNBC as a Smart Cancer Stupid cancers (CML, GIST) have few drivers; smart cancers (cigarette-induced cancers) have many. Mutational load probably determines whether one has a smart or a stupid cancer. DNA damage repair issue are common. And not just in BRCA mutants Somatic rearrangements are common. LOH is common. Dysregulated message is common.

d/t ct2n1 TNBC (ER-/PR-/HER2-) 2014. 08.

44 Neoadjuvant AC #4 + DP (docetaxel + cisplatin) #4 d/t ct2n1 TNBC (ER-/PR-/HER2-) Right TM with ALND ypt2n1 with SD Adjuvant RT 50 cgy/25 Fx s

45 Newly developed multiple subcutaneous nodules

46 Palliative Paclitaxel + Bevacizumab #

47 Neoadjuvant AC #4 + D #4 d/t ct3n2 TNBC (ER-/PR-/HER2-) Right PM with SLNB ypt2n Adjuvant RT 6040 cgy/28 Fx s

48 low abdominal wall mass detect

49 TP (Paclitaxel + Cisplatin) # GP (Gemcitabine + Cisplatin) #4

50 TNBC Very young Poor responsive to neoadjuvant chemotherapy Short DFS Highly aggressive disease course Poor prognosis However, What is difference between the two patients?

52 unclassified or BL1 M Case 1 Case 2 Unclassified LAR IM MSL M LAR BL1 or BL2 Proliferation DNA Damage Response Growth Factor Myopathelial Immune Signal Transduction TGF-beta Signaling EMT Growth Factor Wnt Signaling Stem-like CL Angiogenesis AR-Driven Genes

55 (N=386 ) (N=201) BL1 BL2 IM M MSL LAR Basal-like (~80%) Luminal (10-15%) IM: medullary M & MSL: metaplastic (claudin-low ; high EMT) LAR: apocrine Vanderbilt Subtype

56 TNBC: Low clonality vs. high clonality primary tumors The genomes and transcriptomes of 104 TNBCs Primary TNBCs are still treated as if they were a single disease entity, yet it is clear they do not behave as a single entity in response to current therapies. Treatment-naïve TNBCs display a complete spectrum of mutational and clonal evolution. The clonal heterogeneity of these cancers is also continuum, with some patients presenting with low-clonality cancers and other cases exhibiting more extensive clonal evolution at diagnosis. Nature 486, 395-9, 2012

57 Nature 486, 395-9, 2012 well known oncogenes and tumor suppressors

58 Basal vs. Non-Basal HOMD (homozygous deletion), HETD (hemizygous deletion), HLAMP (high-level amplifications) Nature 486, 395-9, 2012

59 The Oncologist 18, , 2013

60 (~80%) (10~15%) Clin Cancer Res 2013; 19,

61 ER/PR- but AR+ Bicalutamide 150 mg qd Screened 424 patients, 12% AR treated on study 0% RR 19% SD > 6 months Median PFS: 12 wks Benefit possible in strongly AR+ Trials with Abiraterone and Ezalutamide ongoing

62 PI3CA mutation are in kinase domain and not helical in contrast ER+ BC BCR 2014; 16, 406

63 Baylor subtype of TNBC 198 TNBC fresh frozen 84 used for discovery 4 main subtypes of TNBC CCR 21, , 2015

64 Luminal AR (10-15%) MES (5-10%) Basal-like Immune Suppressed Basal-like Immune Activated CCR 21, , 2015

65 CCR 21, , 2015

66 CCR 21, , 2015

67 (N=386 ) (N=201) TNBC BL1 BL2 IM M MSL LAR 1977 lymphocyte infiltration & good Px. IM: medullary M & MSL: metaplastic (claudin-low ; high EMT) LAR: apocrine

TNBC is immunogenic? BIG 02-98 Loi S et al.

68 TNBC is immunogenic? BIG Loi S et al. Ann Oncol 25; 1544, 2014, Loi S et al. J Clin Oncol 31; 860, 2013, Ruffell B et al. PNAS 106;

69 Prognostic value of TIL in TNBC from E2197 and E1199 Stromal TIL Intraepithelial TIL Higher stil were associated with better prognosis. For every 10% increment in stil: 14% reduction of risk for recurrence or death (p=0.02) 18% reduction of risk for distant recurrence (p=0.04) 19% reduction of risk of death (p=0.01) Adams S, et al. J Clin Oncol 2014: 32;

positive FOXP3 lymphocytes in peritumoral area

70 FOXP3 expression in TNBC Hypothesis FOXP3-positive Tregs would be clinically relevant in TNBC pts. FOXP3 IHC staining White arrows indicate positive FOXP3 lymphocytes in peritumoral area (Cancer cells and lymphocytes in background) P=0.036 Median mos 16.8 vs months FOXP3 15 FOXP3 15 FOXP3<15 FOXP3<15 PFS Months OS Months Lee S and Park YH, et al. Acta Oncologica 2013: 52; 73-81

71 Cancer Immunol Res 2014: 2; 361 PD-L1 expression in TNBC TNBC Non-TNBC

72 Immune check point

Pts with recurrent or metastatic ER/PgR-/HER2-, PD- L1+

Discontinuation permitted Treat for 24 mos or until PD or

PD-1 antibody with high affinity for receptor Provides

activity (ADCC/CDC) Clinical activity in multiple tumor

74 Pts with recurrent or metastatic ER/PgR-/HER2-, PD- L1+ BC (N = 32) Pembrolizumab 10 mg/kg q2w CR PR or SD Discontinuation permitted Treat for 24 mos or until PD or intolerable toxicity PD Discontinue Pembrolizumab: anti PD-1 antibody with high affinity for receptor Provides dual ligand blockage of PD-L1 and PD-L2 No cytotoxic activity (ADCC/CDC) Clinical activity in multiple tumor types, recent approval in melanoma Nanda R, et al. SABCS Abstract S1-09.

75 Change From Baseline in Sum of Longest Diameter of Target Lesion (%) Confirmed CR (nodal disease) Confirmed PR SD PD Individual Evaluable Pts (n = 23) Nanda R, et al. SABCS Abstract S1-09.

76 Pembrolizumab is safe, tolerable in heavily pretreated, PD-L1 positive advanced TNBC ORR: 18.5% Durable responses Median DOR: not reached (range: wks) 3 responding pts on treatment for 11 mos Phase II study in advanced TNBC planned for 2015

77 Adverse Events in 5%, % N = 32 Any Grade Grade 3-5 Arthralgia Fatigue Myalgia Nausea ALT increased AST increased Diarrhea Erythema Headache (1 patient)

78 Summary What we know: TNBC is heterogeneous Chemotherapy is the same as for other subtypes (for now) Antiangiogenics is still confusing BRCA deficiency may have real therapeutic implications Platinum agents (may not need entire loss of BRCA function) PARP inhibition (so far clearest in BRCA+ breast cancer) What does our increasing understanding of the biology mean for the future of treatment and for trials?

79 BRCA ½ deletion/mutation ATM/ATR mutation PTEN deletion/mutation PIK3CA mutation Notch translocation HER2 mutation FGFR2 amplification EGFR amplification CCR 2014: 20;

80 TNBCs require deeper molecular stratification including rare dominant oncogenic drivers?!

ENFERMEDAD AVANZADA Qué hacemos con el triple negativo? Nuevas aproximaciones

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 Triple Negative