How I Approach Triple Negative Breast Cancer (TNBC) Dr Tan Yew Oo Specialist Medical Oncologist Farrer Park Medical Centre Singapore

Transcription

1 How I Approach Triple Negative Breast Cancer (TNBC) Dr Tan Yew Oo Specialist Medical Oncologist Farrer Park Medical Centre Singapore

2 Connexion: Integrated Healthcare & Hospitality Complex Levels 11 to 20 Hotel Levels 7-16 Medical Centre Level 6 Conference Facilities, Spa and Fitness Centre Level 3 Radiation Oncology /Nuclear Medicine Suite Level 1 Retail Arcade Level 2 Hospital Lobby Level 5 Surgical Suites, ICU Levels 7-10 Inpatient Suites

3 Facilities at a Glance Level 1 Owen Link Shopping (managed by OFHS) Level 2 Hospital Admission Level 2-3 Diagnostics Imaging, Laboratory, 24-Hour Walk-in Clinic, Inpatient Pharmacy, Nuclear Medicine & Radiation Oncology Level 5 Operating & Procedure Rooms, ICU Level 7-10 Inpatient Suites Level 7-16 Medical Suites

4 Patient s Lounge Serenity, Comfort and Private Level 5 Level 3 Level 2

5 Disclaimer The data in this presentation are provided only to facilitate scientific discourse and may refer to products not approved for use, and/or to unapproved uses of products approved in Bangladesh

6 Outline of Talk What is Triple-negative breast cancer (TNBC) Molecular classification of TNBC subtypes Clinical features of TNBC Prognosis of TNBC Treatment options for TNBC Novel therapies for TNBC Take home messages

7 Triple-Negative Breast Cancer

8 Clinical and Molecular Characteristics of Triple-Negative Breast Cancer Clinical and pathological: Usually high grade with tumour infiltrating and lymphocyte infiltrating more common than other subtypes Higher prevalence of germline BRCA mutation compared to other breast cancer subtypes (15% of unselected TNBC) Shorter time to relapse Higher risk for visceral metastases, including brain metastasis Molecular Basal-like subtype is the most common intrinsic subtype by gene expression analysis Heterogeneous: several subtypes with TNBC identified by gene expression analysis BRCA-mutation associated TNBC demonstrates defective DNA repair and thus sensitivity to DNA-damaging agents such as platinum compounds and poly(adp ribose) polymerase (PARP) inhibitors Homologous recombination deficiency can result from diverse factors and may be present in significant proportion of BRCA wild type TNBC Somatic p53 mutations common (60-80%) but clinically actionable aberrations occur in <20% PI3K pathway activation, despite low PI3K mutation, due to PTEN and INPP4B loss and/or amplification of PIK3CA, is common Androgen receptor-positive subtype within TNBC manifests luminal molecular features and may be targeted with antiandrogen therapy Priyanka Sharma The Oncologist 2016;21: Abbreviations: INNPP4B, inositol polyphosphate 4-phosphatase type II PIK phosphatidylinositol-3-kinase PTEN, phosphatase and tensin homolog

9 Molecular Characterization of Basal-Like and Basal-Like Triple-Negative Breast Cancer Aleix Prat et The Oncologist, 2013;18:123

10 Triple-Negative Breast Cancer: Range of Histology. Clifford A. Hudis, and Luca Gianni The Oncologist 2011;16:1-11

11 TNBC Is not a Single Disease Entity TNBC may be identified in a diverse range of BC types 1 4 Claudin low a Other subtypes Basal Molecular subtypes TNBC (10 24% of BC) BRCA status BRCA mutation BRCAdeficient function Normal BRCA function Ductal NOS Histological and clinicopathological features Medullary Inflammatory Metaplastic Noninflammatory a Newly identified molecular subtype comprising 7 14% of BC; claudins are transmembrane proteins that play critical roles in tight junction formation 2 1. Carey et al. Nat Rev Clin Oncol 2010; 2. Prat et al. Breast Cancer Res 2010; 3. Gluz et al. Ann Oncol 2009; 4. Ashworth et al. JCO 2008

12 Proposed Molecular Subtypes of TNBC Mesenchymal stem cell-like (ML) TNBC Normal M Low proliferation Immune signature Claudin- Low EMT signature: cell motility growth factor signaling (TFG6, Notch, Wnt/β-catenin, Hedgehog) MSL Growth signaling (EGF, IGF) BL2 IM Angiogenesis Basallike cytokeratine BL1 Cell cycle DNA damage BL Immune-associated (IM) TNBC Basallike (BL) TNBC Luminal Androgen Receptor/apocrine (LA) TNBC Lehmann s classification PAM50/claudin-low classification LA/LB PI3K mutations AR pathway LAR HER2e HER2-enriched (HER2e) TNBC Le Du F. Oncotarget. 2015;6:

13 Clinical Outlook in TNBC

14 Clinical Outlook in TNBC

15 Clinical Outlook in TNBC Treatment of TNBC still remains the largest unmet need in breast cancer in spite of extensive research In early stage TNBC, anthracycline and taxanes should be employed in adjuvant therapy In advanced TNBC. No treatments apart from chemotherapy have proven to be effective for this population. Platinum compounds for BRCA-mutated patients The prognosis for TNBC is worse than for other subtypes at all stages of disease Foulkes WD et al N.Engl J Med 2010;363:

16 Clinical Features: Risk of TNBC is Increased in Specific Groups of Individuals Risk factors for TNBC/BLBC 1-9 African American or Hispanic ethnicity a Younger age at diagnosis (<50 years) Lower socio-economic status High parity, young age at time of first birth, lack of breast feeding, use of oral contraceptives (in women <40 years) Increased body weight Metabolic syndrome (particularly high blood glucose, high triglyceride or low HDL level) a The increase in risk may result from biological/genetic factors and/or lifestyle risk factors, including body weight and reproductive factors (multiparity, younger age at menarche, early pregnancy, not breast feeding) 1. Kwan et al. Breast Cancer Res 2009; 2. Millikan et al. Breast Cancer Res Treat 2008; 3. Parise et al. Breast J 2009; 4. Bowen et al. Br J Cancer 2008; 5. Lund et al. Cancer 2008; 6. Morris et al. Cancer 2007; 7. Agurs-Collins et al. Semin Oncol 2010; 8. Trivers et al. Cancer Causes Control 2009; 9. Stead et al. Breast Cancer Res

17 Treatment of TNBC- Current Status Cytotoxic chemotherapy remains the mainstay of treatment for patients with mtnbc despite the promise of new targeted and biologic agents: Standard adjuvant and neoadjuvant regimens include an anthracycline, cyclophosphamide and taxanes Several agents showed activity in metastatic disease: taxanes, eribulin, ixabepilone, gemcitabine, vinorelbine, capecitabine and liposomal doxorubicin Platinum therapy o Addition of platinum agents result in higher pcr rates in neoadjuvant setting¹ o Carboplatin is active in metastatic TNBC with germline BRCA1 and BRCA2 mutations² 1. Sikor WM et al JClinOnc 2015;33: Tutt A et al SABCS 2014; abst S3-01

18 Current Treatment Options for Metastatic TNBC Sequential single-agent chemotherapy is the preferred approach for most pts with metastatic TNBC - Combination chemotherapy can be used for pts requiring more rapid response but does not improve OS Taxanes Anthracyclines Antimetabolites Other Microtubule Inhibitors Platinum Agents Paclitaxel Nab-paclitaxel Docetaxel Doxorubicin Pegylated liposomal doxorubicin Epirubicin Capecitabine Gemcitabine Vinorelbine Eribulin Ixabepilone Carboplatin Cisplatin Patients should generally remain on a regimen until best response, disease progression, or significant toxicity Zeichner SB, et al. Breast Cancer (Auckl). 2016;10: Wahba HA, et al. Cancer Biol Med. 2015;12:

19 Diagnosis of Triple-Negative Disease Genetic Counselling and BRCA Mutation Status Testing Should be Discussed with Patient Sequential Single-Agent Chemotherapy Combination Chemotherapy (Patients with Rapid Progression, Visceral Crisis, Need for Rapid Symptom/Disease Control Previously Untreated with Anthracycline or Taxanes Previously Treated with Anthracycline or Taxanes Anthracycline or Taxane BRCA Mutation BRCA Wild-Type PARPi Carboplatin Eribulin Vinorelbine Capecitabine Note: Include in clinical trials when available ABC: advanced breast cancer, PARPi: poly adenosine diphosphate ribose polymerase inhibitor

20 Clinical Practice Guidelines in Advanced Breast Cancer

21 Treatment Options of TNBC New Targets Treatment of chemonaïve triple-negative breast cancer (including Stage IV) Treatment of refractory triple-negative breast cancer New targets - Angiogenesis - DNA repair - PD-1, PD-L1 and PD-L2 - PI3K/AKT/mTOR pathway - Androgen receptor (AR) - Antibody drug conjugate - Other targets or vaccine-directed

22 Bevacizumab Has Been Studied Extensively in Patients With Advanced TNBC >1000 patients with locally recurrent/metastatic TNBC received Bevacizumab in the pivotal trials programme, including four randomised trials and one large safety study in the routine oncology practice setting 948 patients with TNBC received first-line Bevacizumab in combination with chemotherapy E2100 AVADO RIBBON-1 ATHENA 112 patients with TNBC received second-line Bevacizumab in combination with chemotherapy RIBBON-2 22

23 E2100: Pivotal Trial of Avastin With Paclitaxel Primary endpoint: PFS Other endpoints: ORR, OS, quality of life, safety Previously untreated LR/mBC n=722 TNBC: n=110 Paclitaxel a TNBC: n=122 Paclitaxel a + Avastin 10 mg/kg q2w Treat to PD, no crossover permitted Treat to PD E2100 included 232 patients with TNBC (32%) 1,2 a 90 mg/m 2 weekly for 3 weeks of a 4-week cycle; LR = locally recurrent; PD = progressive disease 1. Miller et al. N Engl J Med 2007; 2. O Shaughnessy et al. SABCS 2010

24 AVADO: Double-Blind, Placebo-Controlled Trial of Avastin combined with Docetaxel TNBC: n=52 Previously untreated LR/mBC n=736 Docetaxel a + placebo q3w TNBC: n=53 b Docetaxel a + Avastin 7.5 mg/kg q3w TNBC: n=58 c Docetaxel a + Avastin 15 mg/kg q3w Treat with placebo to PD or unblinding Treat with Avastin to PD Possible open-label Avastin to PD after unblinding All patients given option to receive Avastin with 2nd-line chemo Primary endpoint: PFS Other endpoints: ORR, duration of response, time to treatment failure, OS, 1-year OS, safety, quality of life AVADO included 110 patients with TNBC (15%) 1,2 a 100 mg/m 2, maximum 9 cycles. b Avastin 7.5 mg/kg arm not included in meta-analysis. c 59 patients in earlier analyses of AVADO (one patient excluded after further review). 1. Miles et al. J Clin Oncol 2010; 2. O Shaughnessy et al. SABCS 2010

25 Estimated probability TNBC Meta-analysis: Kaplan-Meier Estimate of PFS 1.0 Treatment 1 Bevacizumab + chemotherapy (n=353) Median (months) (95% CI) 8.1 ( ) 0.8 Chemotherapy alone (n=258) 5.4 ( ) Unstratified hazard ratio = (95% CI ) p< Stratified hazard ratio = (95% CI ) p= Time (months) No. at risk: Bevacizumab + chemo Chemo alone O Shaughnessy et al. SABCS 2010

26 TNBC Meta-Analysis: Conclusions Subpopulation analyses of patients with TNBC treated in Phase III trials of first-line Bevacizumab demonstrated median PFS ranging from 6.1 months (RIBBON-1 Capecitabine cohort) to 10.6 months (E2100, Bevacizumab combined with weekly paclitaxel) 1,2 The meta-analysis of 621 patients represents the largest reported population of patients randomised to treatment for locally recurrent/metastatic TNBC 3 - Patients were treated exclusively in the first-line setting PFS and response rate were significantly improved when Bevacizumab was combined with chemotherapy, indicating a benefit of Bevacizumab in this population of patients with limited treatment options - The median PFS of 8.1 months represents encouraging efficacy in TNBC, a setting in which median PFS typically ranges from 2 to 6 months 4 10 No significant improvement in OS was observed with Bevacizumab First-line chemotherapy combined with Bevacizumab is more effective than chemotherapy alone in mtnbc 1. O Shaughnessy et al. SABCS 2009; 2. Glaspy et al. EBCC 2010; 3. O Shaughnessy et al. SABCS 2010; 4. O Shaughnessy et al. ESMO 2010; 5. Baselga et al. ESMO 2010; 6. Awada et al. ESMO 2010; 7. Roché et al. ESMO 2010; 8. Roché et al. ESMO 2010; 9. Sirohi et al. Ann Oncol 2008; 10. Uhm et al. Int J Cancer 2009

27 Genomic Alterations in Triple-Negative Breast Cancer Presented By Antoinette Tan at 2015 ASCO Annual Meeting

28 Platinum Forms Adducts that also Arrest DNA Replication Forks and Require BRCA1/2 for Repair

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30 OlympiAD recruited patients between March 2014 and October Over 300 patients enrolled over a period of 19 months in 19 countries 1-3 Region olaparib 300mg N (%) chemothera py N (%) Total N (%) Asia 59 (28.8) 28 (28.9) 87 (28.8) Europe 97 (47.3) 45 (46.4) 142 (47.0) North and South America 49 (23.9) 24 (24.7) 73 (24.2) Robson, M et al N Engl J Med 2017; 377:

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33 Conclusions of OlympiAD OlympiAD provides the first Phase 3 data for a PARP inhibitor in gbrcam HER2 negative MBC and confirms that the benefit of PARP inhibition in BRCAm patients extends beyond ovarian cancer 1 Olaparib treatment significantly improved PFS (HR=0.58 (95% CI ), p=0.0009) compared with Treatment of Physicians Choice (TPC), when assessed by BICR, improving median PFS by 69% from 4.2 to 7.0 months 1 Secondary endpoints also demonstrated statistically and clinically significant benefits of treatment with olaparib compared to TPC: PFS2 was significantly prolonged in patients receiving olaparib (HR=0.57 [95% CI 0.40, 0.83] p=0.0033) compared with TPC 1 ORR was doubled from 28.8% in the TPC arm to 59.9% in the olaparib arm 1 The change from baseline in Global Health related quality of life over the course of the study was better for patients receiving olaparib compared to those receiving TPC 1 While OS data are immature, there is no evidence of OS detriment 1 Olaparib tablets were generally well tolerated with the majority of AEs being mild or moderate in severity and consistent with the safety profile seen in previous studies 1,2 Robson, M et al N Engl J Med 2017; 377:

34 PARP Inhibitors in Clinical Development by Route of Administration and Current Clinical Status Agent Company Route of administration Clinical status Olaparib (AZD2281) AstraZeneca/KuDOS Oral Phase I, II, and III Veliparib (ABT-888) Abbott Oral Phase I, II, and III Rucaparib (AG014699) Clovis Oral Phase II Niraparib (MK4827) Tesaro Oral Phase III INO-1001 Inotek IV Phase I Talazoparib (BMN 673) BioMarin Pharmaceutical Oral Phase III Abbreviation: PARP: Poly(ADP-ribose) polymerase

35 Checkpoint Blockade and Cancer CTLA-4 blocking antibodies release an immune checkpoint at the activation step of an immune response to cancer PD-1 blocking antibodies release an immune checkpoint at the effector step of an immune response to cancer Pembrolizumab is a humanized monoclonal IgG4 antibody Binds to PD-1 with high affinity Prevents PD-1 from binding to PD-L1 and PD-L2 Robust antitumor activity and manageable in multiple advanced melanoma 1-5 and other malignancies a Reprinted with permission from Ribas A. N Engl J Med 2012;366: Copyright 2012 Massachusetts Medical Society. Human IgG4 K D : ~29 pm PD-L1 IC 50 : ~ nm PD-L2 IC 50 : ~ nm 1. Hamid O et al. N Engl J Med. 2013;392: ; 2. Robert C et al. Lancet. 2014;384: ; 3. Daud A et al. Presented at: Society for Melanoma Research 2014 Annual Meeting; November 13-16, 2014; Zurich, Switzerland; 4. Robert C et al. Abstract LBA34. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain; 5. Ribas A et al. Presented at: Society for Melanoma Research 2014 Annual Meeting; November 13-16, 2014; Zurich, Switzerland.

36 KEYNOTE-086: Phase 2 Study of Pembrolizumab Monotherapy for mtnbc Loi S et al ESMO 2017

37 PFS (%) OS (%) KEYNOTE-086 (Cohort A): Survival PFS Mos Pts at Risk, n % 24.2% 26.6% 12.3% 13.2% 11.1% Median, Mos (95% CI) Total 2.0 ( ) PD-L1 positive 2.0 ( ) PD-L1 negative 1.9 ( ) Pts at Risk, n OS Mos % 71.0% 65.4% 49.8% 47.5% 52.6% Median, Mos (95% CI) Total 8.9 ( ) PD-L1 positive 8.3 ( ) PD-L1 negative 10.0 (6.2-NR) Adams S, et al. ASCO Abstract 1008.

38 PFS (%) KEYNOTE-086 (Cohort B): Survival Events, n Median PFS, mos (95% CI) 3-mo rate, % 6-mo rate, % ( ) Pts at Risk, n Mos Adams S, et al. ASCO Abstract 1088.

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40 Unanswered Questions

41 Ongoing Trials of PD-1/PD-L1 Inhibitors in mtnbc Phase III Trial Population Investigational Comparator Primary Endpoint KEYNOTE-119 TNBC after 1-2 prior systemic tx for MBC Pembrolizumab Physician s choice Single-agent chemo KEYNOTE-355 TNBC with no previous chemo for MBC Pembrolizumab + chemo Placebo + chemo Part 1: safety Part 2: PFS, OS IMpassion130 TNBC not previously treated for MBC Atezolizumab + nab-paclitaxel Placebo + nab-paclitaxel OS PFS and OS IMpassion131 TNBC not previously treated for MBC Atezolizumab + paclitaxel Placebo + paclitaxel PFS DORA mtnbc following clinical benefit with platinum-based tx Select Phase II Studies Durvalumab + olaparib and durvalumab Study PD-L1+ mtnbc Durvalumab + paclitaxel AEs NCI Trial HDR-deficient mtnbc (with known BRCA status) Veliparib, atezolizumab, or veliparib + atezolizumab SNDX mtnbc with 1-2 previous lines of Tx Entinostat + atezolizumab, or placebo + atezolizumab MORPHEUS PFS PFS MTD, PFS An open-label, multicenter, randomized umbrella study evaluating multiple immunotherapy-based combinations ClinicalTrials.gov.

42 Inhibition of PI3K/AKT/mTOR Pathway Presented By Antoinette Tan at 2015 ASCO Annual Meeting

43 Summary: Targeting the PI3K/AKT Pathway in Triple-Negative Breast Cancer

44 Targeting the Androgen Receptor Pathway in <br />Triple-Negative Breast Cancer Presented By Antoinette Tan at 2015 ASCO Annual Meeting

45 AR + TNBC: Evolving Molecular and Clinical Insights

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47 Sacituzumab Govitecan (IMMU-132) in mtnbc Sacituzumab govitecan is an antibody-drug conjugate (ADC) targets Trop-2, a glycoprotein elevated in various solid cancers including TNBC FDA breakthrough designation status Comprise a toxic payload, SN- 38 which is topoisomerase I-inhibiting drug that causes double-stranded DNA break leading to apoptosis Irinotecan is the prodrug for SN-38 Bardia A et J Clin Oncol 2017;35:

48 Future Therapies Under Investigations Vantictumab (OMP-18R5) is antibody seeking cell surface protein Frizzled receptor targeting the Wnt/ß catenin signalling pathway Research around cancer stem-like cells, which promote tumour growth and resilience using a novel inhibitor for the epigenetic regulator KDM4, which is an enzyme that regulates gene expression and is implicated in the development of triple-negative breast cancer p53/mva vaccine with pembrolizumab

49 Take Home Messages in TNBC/BLBC Molecular heterogeneity of TNBC Current standard treatment options for patients with TNBC remains chemotherapeutic approaches There is no specific drug available for mtnbc today and effective therapy is critically needed However, major changes in treatment options are happening PARP inhibitors demonstrated benefit vs chemotherapy in patients with TNBC and BRCA1/2 mutations Immune checkpoint inhibitors have shown promising efficacy in patients with mtnbc, particularly in previous untreated patients and in combination with chemotherapy Additional targeted therapy is under investigation for newly defined TNBC subtypes A lot of unanswered questions remain in management of TNBC

50 Thank You for Your Attention