Metastatic Hereditary Breast Cancer: What s New? Melinda Telli, M.D. Assistant Professor of Medicine Stanford University School of Medicine

Transcription

1 Metastatic Hereditary Breast Cancer: What s New? Melinda Telli, M.D. Assistant Professor of Medicine Stanford University School of Medicine

2 Outline Treatment principles in metastatic breast cancer Update on chemotherapy Platinum Lurbinectedin (PM01183) Update on PARP inhibitors in BRCA1/2 and beyond Veliparib Talazoparib (BMN-673) Olaparib Niraparib Update on immunotherapy

3 Goals of Care in Advanced Breast Cancer Metastatic breast cancer is (generally) considered incurable The course of advanced breast cancer is variable Goals of treatment include: Prolongation of survival Palliation of symptoms Prevention of cancer-related complications Maintenance of quality of life

4 How do we define benefit in advanced breast cancer? Overall survival: How long a woman lives Progression-free survival: How long a woman lives without experiencing worsening of her cancer on a specific drug therapy Objective response rate: The proportion of women with measurable tumor shrinkage of at least 30% on a specific drug therapy Clinical benefit rate: The proportion of women with measurable tumor shrinkage or no tumor growth on a specific drug therapy Quality of life: How a woman manages day-to-day with her ongoing therapy; burden of symptoms from disease & treatment

5 Individualizing Therapies for Cancers Patients with the same diagnosis Standard therapy Therapies based on biomarkers

6 Important subsets of breast cancers defined by molecular markers ER+ All Breast Cancer HER2+ BRCA+ Take away: Breast cancer is not one disease Triple negative Germline BRCA1/2 status proving to be an important biomarker for treatment

7 BRCA1 / BRCA2 Positive Breast Cancer The Problem: Information from BRCA1/2 testing does NOT guide treatment decisions in 2015 Responses to standard chemotherapy drugs in carriers not well characterized PARP inhibitors shown to be highly active in advanced BRCA+ breast cancer, but no drugs FDA approved Many patients with hereditary predisposition do not know it High Grade

8 Current role of BRCA1/2 mutation testing Guides screening recommendations Guides surgical risk-reducing recommendations Does not guide treatment BRCA1/2 mutation-associated breast cancer continues to be treated systemically according to the same algorithm for the treatment of sporadic breast cancer

9 Homologous recombination DNA repair defects in breast cancer HR deficiency characterizes breast cancers in BRCA1/2 mutation carriers Due to loss of heterozygosity at BRCA1 or BRCA2 HR deficiency implicated in sporadic TNBC Methylation Somatic mutation Other epigenetic mechanisms Roy R, et al. Nat Rev Cancer Dec 23;12(1):68-78

10 Breast Cancer Genes: The Landscape Foulkes N Engl J Med 2008

11 Rise of the germline mul0plex panel Reference: Domchek SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility. JCO:2013;31:p1268

12 HBOC: BRCA1, BRCA2 and beyond Castera L, et al. European journal of human genetics. 2014;22(11):

13 Chemotherapy

14 Platinum Cisplatin first approved by the FDA in 1978 Noted to have activity in metastatic breast cancer 1 Family of platinum salts bind directly to DNA Results in formation of DNA-platinum adducts and consequently intra- and inter-strand DNA crosslinks that impede cell division Recent renewed interest in investigating the role of platinum chemotherapy in breast cancer Hypothesis of greater susceptibility of TN and BRCA1/2 mutant BC to DNA damaging chemotherapeutic agents Limited data in metastatic disease; most important insights from neoadjuvant setting 1. Sledge, et al. JCO, 1988

15 Platinum in BRCA1/2 mutant breast cancer Proof-of-concept neoadjuvant study of 25 BRCA1 mutation carriers (80% TNBC) 1 pcr rate of 72% with single agent cisplatin 75 mg/m 2 every 21 days x 4 Rate of pcr to standard anthracycline/taxanebased therapy in BRCA1/2 carriers not well known Retrospective data from MDACC: pcr rate of 37% in BRCA1/2 mutation carriers with TNBC 2 Retrospective data from Israel: pcr of 67% vs. 37% in BRCA1/2 positive vs. negative treated with AC-T dose dense 1. Gronwald, et al. JCO, 2009 (abstract); 2. Arun B, et al. JCO, 2011; 3. Paluch-Shimon, et al; ASCO 2014 Abstract 1023

16 Platinum in metastatic BRCA1/2 mutation-positive breast cancer Randomized data comparing platinum to other standard chemotherapies limited First randomized trial in TNBC reported in 2014! Cross-study comparisons difficult Almost no BRCA specific trials -> mostly subsets BRCA1/2 status largely unassessed in our historical literature

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24 Lurbinectedin (PM01183) Novel marine-derived DNA damaging chemotherapy agent Binds DNA in a different way than platinum drugs Pre-clinically, has activity in platinum resistance Early clinical experience in BRCA1/2 mutation-positive advanced breast cancer promising Presented at SABCS in December 2014

25 Binding to the DNA Minor/Major Groove PM01183 Cisplatin

26 PM1183-B Trial - Design Primary endpoint: Overall Response rate BRCA 1 / 2 deleterious mutation 4/20 pts with response 53 pts MBC Ductal/Lobular 1-3 prior CHT (advanced) PS: 0-1 Unknown or non BRCA 1/2 deleterious mutation Interim analysis (20 pts) if 3/30 pts with response Previous platinum therapy allowed Recent amendment excludes prior PARPi 64 pts Interim analysis (30 pts)

27 U.S. Sites SITES Dana Farber Cancer Institute/ Mass General Hospital/ Beth Israel Deaconess Boston, MA INVESTIGATOR Dr. Steven Isakoff Open to accrual M.D. Anderson Houston, TX Stanford University Stanford, CA University of Pennsylvania Philadelphia, PA Dr. Banu K. Arun Dr. Melinda L. Telli Dr. Susan M. Domchek Open to accrual Open to accrual Open to accrual Weill Cornell Medical College New York, NY Dr. Linda T. Vahdat Open to accrual

28 PM01183 Interim Efficacy Data Balmana J, et al. SABCS 2014; abstract P

29 PM01183 Interim Efficacy Data Balmana J, et al. SABCS 2014; abstract P

30 PARP inhibitors in BRCA1/2 mutation-associated breast cancer and beyond

31 PARP1/2 Function Key enzymes involved in repair of single strand DNA breaks PARP is required for the repair of oxidative DNA damageassociated DNA breaks via base excision repair (BER)

32 BRCA1 and 2 deficient cells are markedly sensitive to inhibition of PARP BRCA1-/- BRCA2-/- BRCA2-/- Loss of BRCA + Loss of PARP1 = Synthetic Lethal Interaction Farmer et al. Nature 434:917 (2005) Bryant et al. Nature 434:913 (2005)

33 PARP inhibitiors in advanced BRCA mutant breast cancer: Initial proof-of-concept Olaparib: Superior activity at higher dose 400 mg po BID 100 mg po BID Tutt A. Lancet. Published online July 6, 2010

34 Responses in BRCA 1/2 Carriers irrespective of subtype Tutt A. Lancet. Published online July 6, 2010

35 PARP Inhibitor Development Olaparib FDA approved on December 19, 2014 for advanced BRCA+ ovarian cancer SUCCESS! No FDA approved agents in breast cancer Has been difficult for patients to access these drugs despite encouraging data in the heavily pre-treated setting Failure of the phase 3 iniparib study in metastatic TNBC dampened enthusiasm Realization that iniparib was not a bone fide PARP inhibitor did not help Multiple ongoing randomized clinical trials Combination chemotherapy +/- PARP inhibitor Multiple studies of single agent PARP inhibitor versus treatment-ofphysician s choice Accrual remains challenging Availability of multiple single arm, non-randomized studies limits the pool for randomized trials

36 PARP inhibitors in advanced clinical development for BRCA1/2+ metastatic breast cancer Compound Other names Phase of testing Veliparib (AbbVie) ABT-888 Large randomized phase II completed accrual 3/2015 III ongoing Olaparib (AstraZeneca) KU , AZD2281 III ongoing Niraparib (Tesaro) MK4827 III ongoing III ongoing Talazoparib (BioMarin) BMN 673 Phase II in previously platinumtreated ongoing Phase II for other hereditary mutations newly opened

37 AbbVie M BROCADE Study Design Patient Population Men and women 18 years of age Recurrent or metastatic breast cancer BRCA1 or BRCA2 mutation No prior therapy with carboplatin or cisplatin or with a PARP inhibitor Randomization 1:1:1 N = 85 Veliparib BID + Temozolomide N = 85 Placebo BID + Carboplatin/Paclitaxel N = 85 Veliparib BID + Carboplatin/ Paclitaxel Outcomes Measured Primary Endpoint Progression Free Survival Secondary Endpoints Overall Survival Clinical Benefit Rate Objective Response Rate Peripheral Neuropathy Safety and Tolerability No history of CNS metastases Phase 2 trial completed accrual in March 2015 Phase 3 trial is open & will compare arms M Patient Awareness Presentation Date September 2013 Company Confidential

38 M Study Population Approximately 255 participants will be enrolled in this study at approximately 85 sites throughout the world Patient Population Men and women 18 years of age Recurrent or metastatic breast cancer BRCA1 or BRCA2 mutation No prior therapy with carboplatin or cisplatin or with a PARP inhibitor No history of CNS metastases M Patient Awareness Presentation Date September 2013 Company Confidential

39 Phase III OLympiAD Trial (OLaparib in Advanced Disease) Metastatic germline BRCA+ breast cancer Prior anthracycline/ taxane 0-2 prior tx for mbc No prior platinum Physician s choice (capecitabine, vinorelbine, eribulin) Olaparib Primary endpoint: PFS (no cross-over) Secondary: OS, PFS2 Planned sample size: 310 patients

40 BRAVO trial design Metasta2c or locally advanced anthracycline and taxane pretreated breast cancer pa2ents, HER2 nega2ve with increased possibili2es being BRCA1/2 mutated according NCCN criteria. Registra2on 2 weeks maximum Central BRCA tes2ng Yes gbrca mut + No Not eligible Complete screening Randomize Niraparib 300 mg qd 2:1 randomization niraparib : physician's choice tx No cross over is allowed Physician s choice (eribulin, vinorelbine, gemcitabine, or capecitabine) Treat to disease progression Treat to disease progression Primary objec0ve PFS assessed by blinded- central review Secondary objec0ves OS, Safety, TTF, RR, QoL, CD test concordance Co- lead trial (EORTC, BIG HQ) / Pharma partner: TESARO Protocol finalized, group/site feasibility near comple2on FPI an2cipated in US by end of January 2014 and in EU by mid- February 2014

41 BRAVO Breast Design and Objectives Overview ~300 patients with gbrca mut and advanced/metastatic disease Prior anthracycline and/or taxane Up to 2 treatments for advanced/metastatic disease Trial Design Randomized, international study Each cohort is independently randomized 2:1 niraparib to investigator choice of 4 standard of care metastatic breast cancer chemotherapies Daily oral dose of 300 mg niraparib Objectives Primary Objective: PFS Key Secondary Objective: Overall survival Patients must not be platinum resistant defined as: progression of cancer during or within 6 months of prior platinum treatment 41

42 - Study Design and Plan Open-label, 2-arm, 2:1 randomized trial of BMN 673 versus Protocol-specific physician s choice for locally advanced and/or metastatic BRCA+ breast cancer Protocol-specific physician s choice single-agent chemotherapy options Capecitabine, Eribulin, Gemcitabine, Vinorelbine confidential June1,

43 - Key Eligibility Criteria Inclusion Histologically or cytologically confirmed carcinoma of breast Locally advanced and/or metastatic disease appropriate for single cytotoxic chemotherapy Documentation of deleterious or pathogenic germline BRCA1 or BRCA2 mutation from Myriad Genetics or other laboratory approved by BioMarin No more than 2 prior chemotherapy regimens (metastatic setting) Prior treatment with a taxane and/or anthracycline Measurable or non-measurable disease ECOG < 1 Adequate organ function Exclusion Prior treatment with PARP inhibitor Not a candidate for treatment with at least 1 of the protocol specified comparators Prior platinum treatment in metastatic setting (must be relapse-free x 12 months if given in adjuvant setting) CNS metastasis (except if treated and stable without steroids) Prior malignancy except for prior BRCAassociated cancer as long as there is no current evidence; carcinoma in situ of cervix or non-melanoma skin cancer; cancer diagnosed and treated >5 years prior to study with no further evidence Known to be HIV positive, HER2 positive, active hepatitis B or C virus confidential June1,

44 - Phase 2 study Primary Objective: Determine the overall response rate (ORR) for each cohort treated with BMN-673 as a single agent Study Design: Open-label, 2 cohort study of BMN-673 in locally advanced or metastatic breast cancer patients with deleterious germline BRCA mutations Cohort 1: Patients who previously responded to a platinumcontaining regimen for metastatic disease Cohort 2: Patients who received > 2 prior regimens that do not include platinum for metastatic disease confidential June1,

45 TBB Trial: Talazoparib Beyond BRCA Anosheh Afghahi, M.D. & Melinda Telli, M.D. COHORT B OPEN A Phase II clinical trial of talazoparib in BRCA1 and BRCA2 negative patients with: A. advanced triple-negative breast cancer and homologous recombination deficiency as assessed by the HRD assay B. advanced HER2-negative breast cancer with either a germline or somatic mutation in homologous recombination pathway genes Study design: Single arm, phase II clinical trial PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL)

46 TBB Schema Comprehensive BRCA1 and BRCA2 germline mutation testing Triple-negative without germline mutation in BRCA1 or BRCA2 No germline BRCA1 or BRCA2 mutation but with another germline or somatic mutation in HR pathway (e.g. ATM, PALB2) Germline BRCA1 or BRCA2 mutation HRD assay score < 42 HRD assay score 42 Not eligible for the trial Excluded from the trial Cohort A Accrue 10 patients Cohort B Accrue 10 patients 1 objective response No objective response 1 objective response No objective response Accrue an additional 19 patients End Cohort A of trial Accrue an additional 19 patients End Cohort B of trial Abbreviation: HR (D), Homologous Recombination (Deficiency)

47 Update on immunotherapy

48 Immune Checkpoint Blockade A paradigm shift in cancer therapy Doesn t target tumor cells specifically Works by blocking inhibitory pathways to unleash the body s anti-tumor immune response Adapted from J Allison ASCO 2015

49 FDA Approvals of Antibodies Targeting Immune Checkpoints 2011 Ipilimumab CTLA-4 Melanoma 2014 Pembrolizumab PD-1 Melanoma 2014 Nivolumab PD-1 Melanoma 2015 Nivolumab PD-1 Lung Cancer 2015+???? Adapted from J Allison ASCO 2015

50 Programmed death 1 (PD-1) is expressed on T cells Inhibits killing by T cells when binds to PD-L1 PD-L1 expressed on tumors or in the tumor microenvironment Many antibody drugs now targeting PD-1 and PD-L1 Impressive activity in melanoma, kidney cancer, lung cancer, others Ribas A. N Engl J Med 2012; 366:

51 Tumor mutational burden and immunogenicity Tumors are immunologically unique due to tumorspecific mutations Tumor-specific mutation represent only a fraction of the total number of mutations in the tumor These tumor specific mutations produce neoantigens Capable of recognition by the immune system

52 Prevalence of mutations across human cancer Alexandrov LB, et al. Nature. 2013;500(7463):415-21

53 Are BRCA1/2 tumors more immunogenic due to higher levels of mutations? BRCA1 and BRCA2 mutation-associated tumors contain high levels of genome instability due to defects in normal DNA repair With increasing mutational burden, there is increased potential that the immune system will recognize a neoantigen in the tumor Could this increased burden of neoantigens render BRCA1/2 tumors more amenable to immunotherapies? No answers yet, but very hot topic Clinical trials to open soon

54 Immune overlap with BRCA1 mutations and genomic instability Recently reported study showed that 7/7 BRCA1 mutant tumors also expressed PD-L1 1 ~20% positive in unselected TNBC 2 Elevated PD-L1 expression in TNBC was significantly associated with DNA repair genes 1 Low expression of BRCA1 Low expression of FANCA CIBERSORT Immune Score significantly correlated with genomic instability 1. Pockaj B, et al. ASCO 2014, abstract Mittendorf E, et al. Cancer Immunol Res Apr;2(4): Vinayak S, Telli ML, et al. SABCS 2014

55 Phase Ib KEYNOTE-012: Pembrolizumab in Advanced TNBC CR Discon2nua2on permiaed Patients with recurrent or metastatic ER-/PR-/HER2- PD-L1+ BC (N = 32) Pembrolizumab 10 mg/kg q2w PR or SD Treat for 24 mos or un2l PD or intolerable toxicity PD Discon2nue Pembrolizumab: anti PD-1 antibody with high affinity for receptor Provides dual ligand blockage of PD-L1 and PD-L2 Clinical activity in multiple tumor types, recent approval in melanoma 58% of screened patients were PD-L1 positive Nanda R, et al. SABCS Abstract S1-09.

56 Pembrolizumab in Advanced TNBC (KEYNOTE-012): Tumor Regression Change From Baseline in Sum of Longest Diameter of Target Lesion (%) Confirmed CR (nodal disease) Confirmed PR SD PD Individual Evaluable Pts Nanda R, et al. SABCS Abstract S1-09.

57 Pembrolizumab in Advanced TNBC (KEYNOTE-012): Conclusions Proof-of-concept demonstrated Objective response rate = 18.5% Median PFS = 1.9 months 9.4% experienced SAEs Durable responses? Median DOR: not reached (range: wks) 3 responding pts on treatment for 11 mos Additional studies in advanced TNBC planned for 2015 Nanda R, et al. SABCS Abstract S1-09.

58 23% of TNBC patients screened were PD-L1 positive Objective response rate = 4/21 (19%) Additional 3 patients with pseudoprogression 11% experienced grade 3 or higher toxicity Phase III study in advanced TNBC planned for 2015 Emens LA, SABCS 2014: Abstract PD1-6; AACR 2015

59 Upcoming immunotherapy studies in advanced TNBC and BRCA+ cancers Compound Target Trial MPDL3280A PD-L1 Phase III study of nabpaclitaxel +/- MPDL3280A in first line metastatic TNBC Open to enrollment MPDL3280A PD-L1 Phase II basket study including one arm for BRCA1/2 mutation positive cancers To open July 2015 Pembrolizumab PD-1 Phase II pembrolizumab monotherapy for metastatic TNBC To open June 2015 MANY more to come soon!

60 Concluding Remarks Many exciting new agents are currently under investigation in advanced hereditary breast cancer The TNT trial demonstrated that carboplatin results in superior response rates and progression-free survival compared to docetaxel in BRCA1/2+ metastatic TNBC Practice changing!

61 Concluding Remarks Hope to see PARP inhibitors approved soon! New trials of PARP inhibitors targeting less frequent mutations associated with hereditary breast cancer will be interesting: PALB2, ATM, BARD1, BRIP1, etc. Immunotherapy approaches may prove particularly relevant for BRCA1/2 mutation carriers Urgently need clinical trials in this space

62 Thank you! Question & Answer

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