Triple negative breast cancer - are we making progress -

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1 Triple negative breast cancer - are we making progress - Aleksandra Filipovic MD PhD UMOS Belgrade, Serbia May 16 th, 2015

2 Contents Introduction / definition Current treatments for triple-negative breast cancers Other targets for treatment of triplenegative breast cancers Conclusions

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4 Basal-Like Carcinoma not a complete overlap with TNBC Sub-type from gene expression profiling Cytokeratines 5/6/17 or 14 + (CK8/18-) : 0,8% Combined (CK 8/18+ ) : 10 % Particular morphotype and immunophenotype:central necrosis (74%) Pushing margins (60%) Grade III / high mitotic index RO-/ RP-/ HER2-/ p53 + / EGFR + (41%) or c-kit+ (31%)

5 Challenges in treating TNBC Absence of biomarkers Aggressive natural history Propensity for early visceral metastasis Paradoxical response to chemotherapy BRCA-1 pathway activity (DNA repair, cell cycle check point responses) may be impaired

6 7 different molecular subtypes

7 How might we target each subtype? Basal-like 1 and 2: DNA damaging agents, growth factor inhibition (i.e. EGFR) Immunomodulatory:? Immune regulators Mesenchymal and mesenchymal / stem cell: PI3K/mTOR pathway LAR: Androgen blockade

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9 Targets for TNBC Proliferation anthracyclines p-53 taxanes Genetic instability DNA-damaging agents (platinum compounds,... ) Angiogenesis EGF-R c-kit Targeted therapies

10 something old something new Neoadjuvant Adjuvant Metastatic

11 Fever Nausea Infusional reactions Oral complications Diarrhea Anemia Neuropathy Alopecia Rash, Extravasation Chemotherapy: Adverse events Emotional Cardiac Secondary Malignancies Fatigue Neuropathy Arthropathy Toxicity Activity

12 Current Treatments for TNBC Traditional Adjuvant Chemotherapy : Anthracycline + alkylating agent, followed by taxane doxorubicin + cyclophosphamide followed by paclitaxel CMF a comeback in TNBC CMF reduces locoregional recurrence rate and prolongs DFS in LN-ve TNBC, tumours > 2 cm N = months (range months) decreased recurrence compared to anthracycline- or taxane- (RR = 0.66, 95%; CI ; P = 0.030) CMF regimens for TNBC patients may be more effective than anthracyclineor taxane-based regimens

13 TNBC Paradox : Chemotherapy pcr rates: TNBC ~20 30%; non-tnbc ~5 15%; (P =.034) 3-yr DFS and OS lower in TNBC vs non-tnbc; (P<.0001) N > 1000

14 Highest rates of pcr are seen in HER2 +ve and TNBC

15 Characteristics of Residual Disease Post NAC

16 Need for Post-NAC Residual Disease Trials EA1131: A randomized phase III post-operative trial of platinum chemotherapy vs observation in patients with residual TNBC post-neoadjuvant chemotherapy

17 Clinical Trials with Platinum

18 Neoadjuvant Carboplatin for TNBC Summary of recent randomized trials GeparSixto Study Design N ALLIANCE x2 design npldox/pac/bev +/- wcb (AUC1.5) X 18 wks wpac +/- Cb (AUC 6) +/- bev AC X 4 pcr Control Platinum % 53.2% % 54% ISPY2 wpac+/-cb/veliparib ACx %(est) 52%(est) Both GeparSixto and CALGB included Bev along with Cb and I spy included PARPi von Minckwitz, Lancet Oncol 2014; 15: ; Sikov, SABCS 2013; Rugo SABCS 2013; Alba, BCRT, 2012 (136)

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

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21 Veliparib/Carboplatin GRADUATES in the Triple Negative Signature SIGNATURE Estimated pcr Rate (95% probability interval) Veliparib/ Carbo Concurrent Control Probability Veliparib + Carbo is Superior to Control Predictive Probability of Success in Phase 3 All HER2-33% (22-43%) 22% (10-35%) 92% 55% HR+/HER2-14% (4-27%) 19% (6-35%) 28% 9% HR-/HER2-52% (35-69%) 26% (11-40%) 99% 90% Rugo et. al. SABCS 2013

22 Impact of BRCA1/2 Mutation Status on Response to Platinum-Based Chemotherapy in Triple-Negative Breast Cancer in the TBCRC009 Trial The TBCRC009 phase II trial evaluated single-agent cisplatin or carboplatin as first- or second-line therapy for metastatic TNBC All Patients n=86 BRCA1/2 Positive n=11 BRCA1/2 WT n=65 Unknown n=10 ORR 30.2% 54.6%* 26.2% 30% Median PFS 88 days 96 days 86 days -- * P=.079 versus BRCA1/2 WT 6 patients (7%) are long-term survivors who achieved durable responses and remain off all therapy ( months); all of these patients are BRCA1/2 WT (5) or unknown (1), and received platinum therapy as first-line treatment for MBC Isakoff et al., SABCS 2012; abstract PD-09-03

23 Efficacy of Ixabepilone in Triple-negative Breast Cancer: Subgroup Analyses from Phase II Trials

24 Ixabepilone + Capecitabine Active inixabepilone + Capecitabine Active in Triple-Negative AnthracyclineandTriple-Negative Anthracycline-and Taxane-Resistant MBCTaxane-Resistant MBC

25 PARP1 inhibition DNA-repair defect characteristics of BRCA1-related cancers confer sensitivity to bi-functional alkylating agents, mitomycinc and platinum drugs Defective BCRA1 function could be more specifically targeted Rationale in triple-negative population: evidence of deficient BRCA1 in vitro data showing activity of PARP1 inhibitors in BRCA1 null cells Phase I/II studies ongoing

26 Other targets for treatment of triple- negative breast cancers Treatment Directed Against Angiogenesis Bevacizumab, sunitinib Rationale in triple-negative population: highly angiogenic phenotype responses for heavily pretreated patients during early phase II trials Phase II/III studies ongoing

27 Bevacizumab Activity, 2 first line trialspaclitaxel +/- Bevacizumab (Miller NEJM 2007) Docetaxel +/- Bevacizumab (AVADO ASCO 2008) Completed trials, analysis pending RIBBON I first line - Docetaxel +/- Bevacizumab - Anthracycline-based +/- Bevacizumab - Capecitabine +/- Bevacizumab RIBBON II second line - Capecitabine +/- Bevacizumab

28 Metastatic Breast Cancer Phase III Paclitaxel versus Paclitaxel + Bevacizumab (ECOG 2100)

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31 Treatment targeting EGFR Cetuximab, gefitinib, erlotinib Rationale in triple-negative population: overexpression of EGFR no evidence of activity to date Phase II studies ongoing

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34 Other combinations Gemcitabine + erlotinib Post A et T ORR 25% Paclitaxel + cetuximab Skin relapse EGFR+

35 TCGA: Molecular Characteristics of TNBC - Provides Fuel for Future Therapeutics P53 mut 84% RB1 mut/loss 20% PIK3CA mut 7% MYC focal gain 40% PTEN loss 35% Global Hypomethylation INPP4B loss 30% Aneuploidy and genomic instability

36 Novel Trials: PI3K inhibition in TNBC

37 Novel Trials: Targeting the Androgen Receptor in TNBC

38 Immunotherapy - the breakthrough KEYNOTE 012 : single agent pembrolizumab 10mg/kg 27 patients with measurable metastatic TNBC overall response rate 18.5%, one (3.7%) complete response four (14.8%) partial responses. seven patients (25.9%) stable disease median duration of response ranging from 15 to 40 months progression-free survival rate at 6 months 23.3% in heavily pretreated patients

39 SWOG Proposed Study TNBC Post NAC PT1C or N+ N=400 R Placebo x 1 year Primary endpoint: DFS MK3475 x 1 year Anti-PD1 antibody A randomized, phase III trial to evaluate the efficacy and safety of MK as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes (>pn1mic) after neoadjuvant chemotherapy

40 Cancer cell Cancer cell Durable response

41 So, Are We Making Progress in TNBC? YES Continued dissection of complex biology Incorporation of genetic Factors in therapeutic choices (ie, BRCA mutations/parpi) Plethora of ongoing clinical trials (Clinicaltrials.gov ~ 120)

42 THANK YOU Hvala mojim uciteljima i kolegama na svom znanju koje sam upila od Vas Aleksandra