Metastatic Triple Negative Breast Cancer: Ongoing Trials. Joan Albanell Hospital del Mar, Barcelona

Transcription

1 Metastatic Triple Negative Breast Cancer: Ongoing Trials Joan Albanell Hospital del Mar, Barcelona

2 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

3

4 Potential Therapeutic Implications of TNBC Subtyping Abramson et al. Cancer 2015

5 ClinicalTrials.Gov (Feb 2015) Searching term: Triple Negative Metastatic Breast Cancer; Excluding ad hoc trials based on Chemo or PARPinh 31 Ongoing Trials (Active, not recruiting; Recruiting; Not yet recruiting) with Targeted Therapy or Immunotherapy No trials with mandatory specific mutations/amplifications TN Subtypes for Elegibility not Observed Lots of biomarker exploratory analysis and planned subsets

6 ClinicalTrials.Gov (Feb 2015) Triple Negative based on traditional ER/PR/HER2 (all comers) (n=23) Growth Factor Receptors: Met (ARQ-197, cabozantinib, onartuzumab (+CT, Beva)); EGFR; Nimotuzumab (+CT), Icotinib; FGFR: Lucitanib PI3K/Akt/mTOR: BKM120, Ipatasertib + paclitaxel, everolimus (+CT), (n=2) MEK: Cometinib + Paclitaxel, Trametinib (andgsk ) CDK inhibitor: Dinaciclib Apoptosis: Abraxane + Tigatuzumab (Death Receptor 5) Stemness: CXCR4 POL ct; Notch/Hedgehog RO vismodegiv; LDE225 (+BKM120/CT) Glutaminase Inhibitor: CB-839 Angiogenesis: ENMD-2076, Apatinib Immunotherapy (PD-L1+?): Nivolumab + CT; Nivolumab + Ipilimumab, Autologous cmet Redirected T Cells Triple Negative and Androgen Receptor Positive (n=5) Bicalutamide (n=2), Enzalutamide, Orterone, 4 OH testosterone Triple Negative and Androgen Receptor Negative (n=1) PI3K: GDC cisplatin Triple Negative EGFR Positive: Gefitinib (n=1) Triple Negative gpnmb Positive: Glembatunumab vedotin (n=1)

7

8 From C Turner ES

9 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

10

11 Andre et al. CCR 2013

12 A new breast cancer subtype? - HER2 Negative (1+ or 2+; FISH negative) - HER3 Positive - ER + or -

13

14 Phase I Pharmacoynamic and Antitumor Data with RG7116 Proc ASCO 2013

15 RT7160 (anti-her3) Combined with Anti-EGFR or Pertuzumab Anti-EGFR + anti-her3 Pertuzumab + anti-her3 HER2 1+/2+ and FISH- / HER3+ trial Mirschberger et al. Cancer Res 2013

16 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

17 PIK3CA Mutations in Basal-like Cancer and by Lehmann s Subtypes

18 PI3K Inhibitors in Development Three generations of PI3K inhibitors have now been developed 1 3 First-generation Second-generation Third-generation Pan-PI3K class I inhibitors Inhibit all four isoforms of class I PI3K (α, β, γ, δ) and provide the broadest inhibition of PI3K 3,6 May be better suited to combination therapy and in tumour types lacking PIK3CA mutations 4 Isoform specific inhibitors Characterised by greater and PI3K isoform-specific activity 3 Provide the potential to completely block a specific target while limiting toxicities associated with a broader inhibition 5 Dual PI3K/mTOR inhibitors Target homologous regions in the catalytic sites of PI3K and downstream components mtorc1 and mtorc2 3,6 Targeting two levels of the pathway may provide the potential advantage of stronger inhibition 3,6 1. Akinlele et al, J Haematol Oncol 2013; 2 Porta et al, Front Oncol 2014; 3. Martini et al, Front Oncol 2013; 4. Dienstmann et al, Mol Can Ther 2014; 5. Fruman and Rommel, Nat Rev Drug Dis 2014; 6. Rodon et al, Nat Rev Clin Oncol 2013; 7. Engelman et al, Nat Rev Cancer 2009; 8. Courtney et al, J Clin Oncol 2010

19 Taselisib, a Selective Inhibitor of PI3Kα and Mutant Variants, Was More Active in PIK3CA-Mutant Breast Cancer Best % SLD Change Taselisib as a single-agent in wild-type and PI3KCA-mutant BC 50 9 mg/g 9 mg/d 9 mg/a 8 mg 5 mg 3 mg 12 mg PD PD PD PD PD SD PD PD SD 1.5 SD SD PD PD PD PD SD SD SD SD SD PD SD PD SD SD PR PR PR PR PR 6.7+ PR # prior tx mo on study Best confirm esp PIK3CA status ORR, % (cpr) Mutant 25 (6/24) Mut, prior fulvestrant 25 (1/4) Wild-type 0 (0/9) PIK3CA mutant PIK3CA wild type HER2 expression Prior Fulvestrant Prior Everolimus Prior Letrozole PR+ PR- In this Phase Ib study PMT4979g, heavily pretreated patients (>4L) with either wild-type or PI3KCA-mutant BC responded to single-agent taselisib Based on measurable disease. Waterfall chart does not include patients with no post-baseline tumor measurements; Data extracted 15 Aug Some data not source-verified. Genentech, data on file.

20 Phase II trial of Everolimus and Carboplatin in TNBC (Sing et al. BCRT 2014) Majority of patients had prior chemo, including carboplatin 1 CR, 6 PR, 7 SD Clinical Benefit 36% (21-57%)

21 Duncan et al. Cell 2012 MEK Inhibitor Trametinib and Akt Inhibitor GSK in Treating Patients With Metastatic Triple-Negative Breast Cancer PART 1: Patients receive trametinib PO QD on days Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK PO QD on days 1-28.

22 HER3 Phosphorylation in TNBC cells in Response to Cetuximab plus Akt or PI3K inhibition (Tao et al. Sci Signal 2015)

23 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

24 Gamma-Secretase Inhibitor (PF ) Clinical Trials Title Phase Status ID Number A Phase 1 Trial of PF in patients with advanced solid tumor malignancy and T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma Phase 1b study of docetaxel + PF in metastatic or locally recurrent/advanced triple negative breast cancer 1 Closed NCT A b Open for recruitment NCT A

25 Phase I Trial Results with the Gamma-Secretase Inhibitor PF (Messersmith et al. CCR 2014)

26 PF Docetaxel Leads to Enhanced Effect in Triple Negative Breast Cancer Models in Part via CSC Inhibition HCC1599 cell line xenograft HCC1599 treated tumors Zhang C, et al. Stem Cells Transl Med 2013;2:

27

28 TLD window 42 days (2 cycles) Treatment till progression, unacceptable toxicity or ICF withdraw GEICAM/ "EDALINE Phase Ib Dose Escalation, Open Label, Multicenter Study Evaluating the Hedgehog Inhibitor LDE225 in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Breast Cancer TN, no more than 3 previous QT treatment lines. Docetaxel IV C3s LDE225 Oral daily ND1 (3-6 patients) Docetaxel 75 mg/m 2 LDE mg Patients. ND2 (3-6 patients) Docetaxel 75 mg/m 2 LDE mg ND3 (3-6 patients) Docetaxel 75 mg/m 2 LDE mg Design 3+3 ND -1 Docetaxel 60 mg/m 2 LDE mg Martín M, et al. ESMO 2014

29 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

30 Gucalp et al. CCR 2013

31 PIK3CA Mutations in AR-Positive TNBC Confers Sensitivity to Combined PI3K and AR Inhibitors (Lehmann et al. BCR 2014) Pan-PI3kinh Dual PI3K/mTOR

32 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

33

34

35

36

37 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

38

39 Metastatic Triple Negative Breast Cancer Spectrum Targeting Growth Factor Receptors Targeting Signaling Transduction Pathways Targeting Stemness Targeting The Androgen Receptor Immune Checkpoint Modulators Dynamics of mtnbc Summary

40 Summary 1. The majority of trials select patients based on traditional triple negative status. 2. The majority of trials included biomarker endpoints or enrichment of subsets. 3. Androgen receptor is the main biomarker used for subtyping TNBC for anti-androgen trials. 4. Increasing preclinical evidence and the limited activity of single agent data with signal transduction inhibitor point to drug combinations and biologically-driven patients selection as an attractive strategy. 5. Targeting stem-like/emt ongoing. Role of Mesenchymal subtype tbd. 6. Immune checkpoint modulators are promising. Role of Basal/Immune subtype and PD1/PD-L1 tbd. 7. Tackling the dynamics of TNBC biology in sequential patient specimens is necessary to better understand this aggressive disease. Aurora as a big effort.