Treatment of Metastatic TRIPLE NEGATIVE BREAST CANCERS. Rebecca Dent, MD FRCP (Canada) Senior Consultant, Medical Oncology

Transcription

1 Treatment of Metastatic TRIPLE NEGATIVE BREAST CANCERS Rebecca Dent, MD FRCP (Canada) Senior Consultant, Medical Oncology

2 Overview of TNBC Still best way to define in clinical practice!?

3 Survival (%) Treatment options and survival vary greatly by breast cancer subtype ER/PR+ 65% TNBC 15% HER2+ 20% Chemotherapy +/-Bevacizumab PARPi (BRCA) Trastuzumab T-DM1 Pertuzumab Lapatinib Neratinib Chemotherapy Metastatic breast cancer survival: SEER data 1,2 HER2+/HR+ (N = 1,293) HER2+/HR (N = 695) 100 HER2 /HR+ (N = 4,590) 80 TNBC (N = 1,000) Tamoxifen Aromatase inhibitors Fulvestrant CDK4/6 inhibitors mtor inhibitors 20 0 Log-rank p< Survival (months) Patients with TNBC have a poorer prognosis than those with other forms of BC 4,5 1. Gong Y, et al. Sci Rep SEER cancer statistics: Accessed August 2017

4 How Can TNBC be Stratified? Perou C, SABCS

5 Number of samples with aberrations Clinically Targetable Pathways in TNBC IMMUNOTHERAPY AKT3 PTEN TSC1 AKT2 AKT1 RAPTOR RICTOR ~90% of all patients had an aberration in at least one of these pathways RB1 CDNK2A CCNE1 CCND3 AURKA ATM CCND2 MET PIK3R1 BRCA2 NF1 CRAF CCND1 BRAF IGF1R PIK3CA BRCA1 CDK6 KRAS CDK4 EGFR PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs FGFR4 FGFR1 KIT FGFR2 PI3K/mTOR/AKT inhibitors DNA-repair targeting agents RAF/MEK inhibitors Cell cycle/mitotic spindle inhibitors Targeted RTK inhibitors Balko JM et al. Cancer Discovery

6 Epidemiology 6 Foulkes WD et al. NEJM 2010.

7 HR HR of Progression & Death: TNBC vs non-tnbc Dent R, CCR 2007 Liedtke C, JCO 2008 Other (290 of 1421) Triple negative (61 of 180) Yrs After First Surgery Median Time to Distant Recurrence TNBC = 2.6 yrs Other = 5 yrs p <

8 Probability of Being Alive Chemosensitivity of TNBC: Post-NACT pcr & Survival von Minckwitz G, JCO 2012 Liedtke C, JCO % 94% 88% P = pcr/non-tnbc pcr/tnbc RD/non-TNBC RD/TNBC 1 68% P = Yrs After Surgery CTneoBC, Lancet

9 9 Kassam F Dent et al BCRT 2009

10 What are the treatment options for metastatic TNBC in 1 st line and beyond? Taxane (+/- Bevacizumab) Nab-paclitaxel Platinum single agent Platinum combination (e.g. Gemcitabine/platinum) Eribulin Capecitabine (+/- Ixabepilone) Vinorelbine (+/- Capecitabine) Anthracycline (including liposomal) Low dose Cyclophosphamide/MTX or CMF Oral etoposide Clinical trials 10

11 HER-2 NEGATIVE MBC If given in the adjuvant setting, a taxane can be reused as 1st line therapy, particularly if there has been at least one year of disease-free survival (LoE: 1 A) (92%).

12 New statement TRIPLE NEGATIVE ABC For non-brca-associated triple negative ABC, there are no data supporting different or specific CT recommendations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC. (LoE: 1 A) Total # of votes: (44) 1. YES: 97.7% (43) 2. NO: 3. ABSTAIN: 0.0% 2.2% (00) (01)?

13 Study 301: Eribulin vs Capecitabine in Previously Treated LABC or MBC 3 prior chemo ( 2 for advanced disease) prior anthracycline & taxane N = 1102 Stratified by geographical region, HER2 status Eribulin Mesylate 1.4 mg/m 2 D1,8 q21d (n = 554) Capecitabine 1250 mg/m 2 BD D1-14 q21d (n = 548) Kaufman PA et al, JCO

14 Study 301: Eribulin vs Capecitabine Subgroup HR (95% CI) Eribulin Capecitabine Median (months) Overall (0.770, 1.003) HER2 status Positive (0.688, 1.355) Negative n= (0.715, 0.983) ER status Positive (0.737, 1.093) Negative n= (0.635, 0.955) Triple negative Yes n= (0.545, 0.906) No (0.795, 1.081) ITT population Favours Eribulin Favours Capecitabine Twelves C et al, Breast Cancer (Auckl) 2016.

15 TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer Tutt A et al. SABCS

16 Response at Cycle 3 or 6 (%) TNT: ORR of Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer P = % 31.4% All Pts (n = 376) P = % 25.6% C D D C Crossover* (All pts; n = 182) Carboplatin Docetaxel Crossover Tutt A et al. SABCS P = % 33.3% BRCA1/2 Mutation (n = 43) *Excludes those with no first progression or not starting crossover treatment. P = % 28.1% No BRCA1/2 Mutation (n = 273)

17 TNT: Platinum Sensitivity Was Not Associated with Higher HRD Scores in mtnbc High HRD score (n = 81) Percentage with OR at #3 or #6 (95% CI) Carboplatin Docetaxel 13/34 (38.2%) 20/47 (42.6%) Absolute difference (C-D) -4.4% (95% CI to 17.2) Exact P = 0.82 Low HRD score (n = 114) Percentage with OR at #3 or #6 (95% CI) Carboplatin Docetaxel 19/65 (29.2%) 17/49 (34.7%) Absolute difference (C-D) -5.4% (95% CI to 11.9) Exact P = 0.55 Interaction: randomised treatment & dichotomised HRD score: P = 0.91 Tutt A et al. SABCS

18 New statement TRIPLE NEGATIVE ABC In triple-negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or without taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favorable toxicity profile, compared to docetaxel, and is therefore an important treatment option. (LoE: 1 A) Total # of votes: (43) 1. YES: 90.6% (39) 2. NO: 3. ABSTAIN: 4.6% 4.6% (02) (02)?

19 Modified statement In patients with BRCA-associated triple negative or endocrine-resistant MBC previously treated with an anthracycline with or without a taxane (in the adjuvant and/or metastatic setting), a platinum regimen is the preferred option, if not previously administered and no suitable clinical trial is available. (LoE: 1 A) BRCA-associated MBC All other treatment recommendations are similar to sporadic MBC. Total # of votes: (44) 1. YES: 86.3% (38) 2. NO: 3. ABSTAIN: 4.5% 9.0% (02) (04)?

20 Olaparib: Phase II Study in gbrca mut Breast Cancer Proof-of-concept phase II trial Olaparib 400 mg BD group: N = 27 67% BRCA1 50% TNBC Median 3 prior lines Tutt A et al. Lancet

21 Olaparib versus physicians choice: the phase III OLYMPIAD study Primary end point: centrally-evaluated PFS Olaparib 300 mg bd Chemotherapy TPC 163 (79.5) 71 (73.2) HR % CI 0.43 to 0.80; P= Robson et al, New Engl J Med 2017

22 Clinical Practice? Not clear how it compares to platinum or if efficacy similar in platinum resistant patients Not recommended in unselected TNBC 22

23 No. mutations/mb Are All Cancers Equally Suitable for Immunotherapy? Somatic mutations in breast cancer subtypes TNBC ER positive Mutation rate higher in TNBC compared to other subtypes Banerji S, et al. Nature. 2012;486(7403): Synonymous Nonsynonymous Luminal A Luminal B HER2 Basal Normal 23

24 Immune Checkpoint Inhibitors in mtnbc Pembrolizumab (n = 32) Atezolizumab (n = 71) Avelumab (n=58 /9) Target PD-1 PD-L1 PD-L1 Tumour PD-L1 1% (58%+) 5% All / 1% ORR 18.5% 13% 8.6% / 44.4% SD 25.9% 18% 22.4% Durable responses in heavily pre-treated pts Nanda et al, JCO 2016; Schmid et al, AACR 2017; Dirix et al, SABCS

25 ORR, % ORR, % Pembrolizumab Antitumor Activity in Previously Treated and Previously Untreated mtnbc Cohort A (N = 170): Previously Treated, Regardless of PD-L1 Expression Cohort B (N = 52) 1 : Previously Untreated, PD-L1 Positive Complete response Partial response Stable disease 24 wk % % 9.5% 4.7% Total PD-L1 Positive PD-L1 Negative 0 Total (All PD-L1 Positive) 25

26 Combination Immune-and Chemotherapy in TNBC Nab-Paclitaxel + anti-pd-l1 (atezolizumab) 1 st line Patients Eribulin + anti-pd-1 (pembrolizumab) 2 nd / 3 rd line Patients Independent of PD-L1 status All 1 st line (n=17) 2 nd /3 rd L (n=18) ORR 34.4% 41.2% 27.3% CBR 40.6% 47.1% 36.4% Adams S, SABCS 2015; Tolaney, S SABCS 2016, ESMO

27 Heterogeneity of TNBC and Immunotherapy Strategies TNBC: Gene expression subtypes (Baylor) Inflamed Basal-like Basal immune activated Single agent immune therapy (eg, PD-1; PD-L1) Basal immune suppressed Mesenchymal Combination immune therapy (eg, PD-1/PD-L1; CTLA4) Luminal AR Adapted from: Burstein MD, et al. Clin Cancer Res. 2015;21(7): Modify antigens? Uninflamed Luminal 27

28 Clinical Practice No evidence of immune check point inhibitors outside of clinical trials (many ongoing!!!) 28

29 DORA Study Design: A Randomized Phase 2 Maintenance study of PARP Inhibition alone vs PARP Inhibition + Anti-PD-L1 therapy Randomised, non-comparator, international, AZ Investigator Initiated Trial And Duke-Singapore/Duke-USA Collaborative Grant for Translational Studies Eligibility: Mets TNBC Response after 4 cycles of platinum chemo as 1 st or 2 nd line therapy R A N D O M I Z E D Olaparib 300mg bid daily Olaparib 300mg bid daily Durvalumab 1500mg q 4 weekly 1 Endpoint = PFS CT q8 weeks R Dent, T Tan and K Blackwell

30 Targeting the Androgen Receptor (AR) in TNBC AR-Driven Biology in TNBC using Gene Expression Profiling Assay Enzalutamide Bicalutamide Enzalutamide RR (%) CBR (%) MDV Cortes J et al, IMPAKT TBCRC011. Gulpa A et al, CCR Parker et al, ASCO

31 Overall Survival (%) Overall Survival (%) Progression-Free Survival (%) Progression-Free Survival (%) Is AR PREDICT picking out good prognosis TNBC? 100 ITT Population Progression-Free Survival 100 Subpopulation 0 1 Prior Regimens Dx+ (n = 56) mpfs 16.1 weeks (95% CI: 10.4, 27.4) Dx+ (n = 26) mpfs 32.3 weeks (95% CI: 14.7, 60.3) Dx (n = 62) mpfs 8.1 weeks (95% CI: 7.4, 12.6) Weeks ITT Population Dx+ (n = 56) mos 21.3 months (95% CI: 12.9, 21.3) 20 0 Overall Survival Dx (n = 36) mpfs 8.3 weeks (95% CI: 7.1, 16.1) Weeks Subpopulation 0 1 Prior Regimens Dx+ (n = 28) mos NYR (95% CI: 14.0, NYR) Dx (n = 62) mos 7.5 months (95% CI: 4.8, 11.2) Weeks Dx Dx (n = 37) mos 10.1 months (95% CI: 6.6, NYR) Weeks Dx 31

32 32 Clinical Practice?

33 LOTUS: AKT Inhibition in mtnbc LABC/MBC No prior systemic therapy for ABC/MBC Archival or newly obtained tumor tissue for central PTEN assessment Chemo-free interval 6 mo N = 124 R 1:1 Paclitaxel 80 mg/m 2 D1, 8, & 15 + Ipatasertib 400 mg OD D1-21 q28d Treatment until PD, intolerable toxicity, or withdrawal of consent Paclitaxel 80 mg/m 2 D1, 8, & 15 + placebo D1-21 q28d Stratified by (Neo)adjuvant chemo (yes vs no) Chemo-free interval ( 12 vs >12 mo vs no prior) Tumour PTEN status (H-score 0 vs vs >150, by Targos IHC) Dent R ASCO 2017; Kim SB et al, Lancet Oncol

34 LOTUS: AKT Inhibition in MBC Dent R ASCO 2017; Kim SB et al, Lancet Oncol

35 PFS (%) LOTUS: AKT Inhibition in MBC PIK3CA/AKT1/PTEN Altered* Ipat + Pac (n = 26) Pbo + Pac (n = 16) PFS events, n (%) 12 (46) 13 (81) mpfs, mos (IQR) 9.0 (3.7-NE) 4.9 ( ) Unstratified HR (90% CI) 0.44 ( ) 20 0 Ipatasertib + Paclitaxel (n = 26) Placebo + Paclitaxel (n = 16) Mos Dent R ASCO 2017; Kim SB et al, Lancet Oncol

36 36 Cell Surface Markers: Targets for Antibody-Drug Conjugates

37 Glembatumab (gpnmb) vedotin (CDX-011): Antibody Drug Conjugates CR011 Ab Cell membrane MMAE vc Linker GPNMB Binding CDX-011 binds to GPNMB on cancer cells Parameter High gpnmb Expression CDX-011 n=25 IC n=8 Triple Negative & High gpnmb Expression CDX-011 n=12 IC N=4 Response 32% 13% 33% 0% Disease Control Rate 64% 38% 75% 25% Cleavage CDX-011 is internalized and the linker is cleaved by endosomal enzymes Tubulin inhibition Free MMAE inhibits tubulin polymerization, leading to cell death Median PFS (months) p=0.14 p=0.008 Median OS (months) p=0.18 p=0.003 Rose AA, et al. CCR

38 RANDOMISE 2:1 METRIC: Ongoing Phase III Trial Pts with mtnbc overexpressing gpnmb ( 25% tumour cells by IHC) N = 300 Glembatumumab vedotin 1.88 mg/kg IV D1 q21d Capecitabine 1250 mg/m 2 BD D1-14 q21d Treat until unacceptable toxicity or PD Tumour assessments (6w intervals x 6 mo; 9w intervals thereafter) until documented PD Survival follow-up (12w intervals) Study at approx sites in US, Canada and Australia Primary endpoint: PFS 38

39 Sacituzumab Govitecan (IMMU-132) Humanised IgG Antibody against Trop-2 Conjugated with a ph-sensitive linker to SN-38 Heavily pretreated TNBC Median number of prior therapies = 4 (1-11) 39

40 Sacituzumab Govitecan: FDA Breakthrough Designation ORR 30% 40 Bardia A et al. JCO 2017.

41 Case AH 38F previously well, nulliparous, no family history Sep cm, Grade 3, 2 LN +, TNBC BRCA negative Treated with AC-weekly paclitaxel completed Jan

42 AH cont 2 years after completion of adjuvant chemotherapy, presents with Cough, SOBOE, nausea and headaches CT CAP multiple pulmonary nodules consistent with metastases, left supraclavicular LN and mediastinal LN CT brain multiple CNS metastases Biopsy of supraclavicular LN = TNBC Treated with Whole brain radiation treatment 42

43 43 CNS & Lung metastases

44 Question 1: What systemic therapy would you offer this patient? (note: recent CNS mets post WBRT, ineligible for trial received adjuvant AC-T 2 years ago) 1. Taxane single agent 2. Eribulin 3. Capecitabine +/- Navelbine 4. Platinum alone 5. Platinum combo (ie. Carbo/Gem) 6. Other 44

45 AH cont Patient treated with 3 cycles of carbo/gem with resolution of cough and SOB and first restaging scan shows response 45

46 After 3 cycles Carbo/Gem 46

47 After 6 cycles, significant myelosuppression, pt requesting break Chemo break Continue carbo/gem until max response or toxicity Continue carboplatin only Switch to maintenance oral cyclo/mtx Switch to maintenance oral capecitabine Switch to other chemo Palliative care 47

48 Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. What is considered unacceptable should be defined together with the patient. (LoE: 1 B) (72%)

49 AH cont Unfortunately after 6 cycles, by the time patient had restaging scans - new onset cough and mild hemoptysis (i.e. patient didn t get opportunity to make decision) 49

50 AH cont What will you offer her? 1. Eribulin 2. Capecitabine +/- Vinorelbine 3. Taxane 4. Liposomal doxorubicin 5. CMF (oral or IV) 6. Palliative Care 7. Other 50

51 AH cont After cycle 1 clinical improvement with resolution of hemoptysis and cough After cycle 3, new onset fever, worsening cough and hemoptysis 51

52 AH cont Patient worked up for pembrolizumab trial, biopsy sent for central review, ER 30% +, thus ineligible for trial And Asx Progression of Brain Metastases 52

53 AH cont Asymptomatic brain metastases minimal burden of disease, opted not to treat What would you offer her now? 53

54 In Practice: Management of Metastatic TNBC No standard chemotherapy mos remains 12mo get pall care early! PARP inhibitors show very promising results await approval for germline BRCA Immunotherapy Await results of ongoing trials Single agent vs combination therapy Need for predictive signature PIK3CA/mTOR/AKT pathway is intriguing Await Phase III data on ADCs Refer tor trials early!! 54

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