Triple negative breast cancer -neoadjuvant and adjuvant systemic therapy

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1 Triple negative breast cancer -neoadjuvant and adjuvant systemic therapy Sung-Bae Kim, MD, PhD Department of Oncology Asan Medical Center University of Ulsan College of Medicine Seoul, Korea

2 DISCLOSURE SLIDE Nothing to declare

3 Outline Preferred chemotherapy regimen Platinum Capecitabine in non-pcr Practical issues -impact of delaying adjuvant CT in TNBC -small tumor -TIL

4 Triple negative breast cancer TNBC = ER (0), PgR (0) and HER2 (IHC 0-1+ or FISH -) TNBC comprises approximately 15-20% of incident breast cancers Generally exhibit poor clinical outcomes BRCA mutations in nearly 20% of TNBC patients (vs 5% in non- TNBC) 16% BRCA1 4% BRCA2 No targeted treatment available for non-brca mutated TNBC Main treatment remains chemotherapy

5 Annual Hazard Rate Clinical Characteristics of TNBC Relapse pattern [1] Short disease-free interval Increase in visceral mets Differs from luminal: CNS mets in 46% of cases Distant Recurrence Following Surgery [3] Other (290 of 1421) Triple negative (61 of 180) Rate of Recurrence [2] n Bone, % Soft Tissue, % Viscera, % TNBC ER Yrs After First Surgery HER Lin NU, et al. Cancer. 2008;113: Liedtke C, et al. J Clin Oncol. 2008;26: Dent R, et al. Clin Cancer Res. 2007;13:

6 TNBCs are heterogenous IDC NOS, high-grade ILC high-grade, pleomorphic Metaplastic, high-grade Myoepithelial carcinoma High-grade (oat-cell) neuroendocrine Apocrine Medullary Adenoid-cystic Metaplastic, low-grade -low grade adenosquamous Firbromatosis -like Poor Prognosis Good Prognosis

7 BEATRICE TRIAL ~2600 early TNBC received adjuvant CT median FU 56Mo: 7% died Cameron et al. Lancet Oncol 2013 Molinero et al. SABCS 2015

8 Adjuvant Chemotherapy Options for HER2-Negative Breast Cancer Warranting Chemotherapy Treatment JAMA Oncol. 2016;2(11):

9 Triple-negative BC Adjuvant therapy Neo-adjuvant therapy

10 Blum JL Clin Oncol 34, 2016 abstr# 1000 Role of Anthracycline: Joint Analysis of the ABC (Anthracyclines in early Breast Cancer) Trials

11 Joint Analysis of the ABC (Anthracyclines in early Breast Cancer) Trials Blum JL Clin Oncol 34, 2016 abstract # 1000

12 CALGB 9344: AC4 Paclitaxel It s All Relative: Taxanes are Effective in Double Negative Hayes D et al. N Engl J Med 2007;357:

13 NSABP B-30: AC4 T4 vs TAC4 vs AT4 8Y OS AC T 83% AT4 79% TAC4 79% 8Y DFS AC T 74 % AT4 69% TAC4 69% Swain SM et al. N Engl J Med 2010;362:

14 Sparano et al. JCO 2015 Standard adjuvant regimen: A/EC x 4 q 21 weekly paclitaxel x 12

15 New standard adjuvant regimen? EC x 4 q 2wks Paclitaxel x 4 q 2wks TNBC patients Del Mastro et al. Lancet 2015

16 Budd et al. JCO2015 Gold standard adjuvant regimen: EC q2wks x4 weekly paclitaxel x 12

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18 pcr as prognostic factor

19 Neoadjuvant Cisplatin (CDDP) in TNBC N = 28, stage II/III triple negative Cisplatin 75 mg/m 2 q3w x 4 cycles Pathologic CR 6 (22%) Clinical CR 4 (14%) Clinical PR 10 (36%) Stable Disease 5 (17%) Not bad for a single agent 15% expected for AC 22% AC-T (B27) Silver DP et al. J Clin Oncol 28 (7): , 2010 N = 30, stage II/III triple negative ECisF paclitaxel 43% in-breast pcr rate Torrisi et al, Cancer Chemother Pharmacol, 2007

20 GeparSixto

21

22 CALGB randomised phase II trial Clinical stage II-III TN Primary EP pcr in breast (trial did not mandate surgery of axilla) *Gcsf primary prophylaxis for ddac cycles Sikov et al, SABCS 2013

23 pcr (carboplatin) pcr breast pcr breast/axilla OR 1.76 (p=0.0018) OR 1.71 (p=0.0029) Sikov et al, SABCS 2013

24 The Role of Platinum in TNBC N pcr in Carbo arm pcr in Control arm P-value CALGB % 41% P=0.003 GeparSixto % 38% P<0.05 I-SPY % 26% 90% probability Pusztai L. SABCS 2013

25 Disease Free Survival GeparSixto (Med FU 35Mo) vs CALGB (Med FU 39Mo)

26 Differences GeparSixto Trial CALGB Trial pcr Without carbo With carbo EFS Without carbo With carbo HR 36.9% 53.2% 76.1% 85.8% 0.56 ( ) Pts prognostic factors ct1 26% cn0 60% Control CT Anthra Taxane Beva Concurrent 360 x 18 wks 1140 x 18 wks All pts 41% 54% 71.6% 76.5% 0.84 ( ) ct1 11% cn0 42% Sequential 240 x 12 wks 960 x 12 wks One arm Carbo dose/schedule AUC 2 or 1.5 weekly AUC 6 q 3 wks Higher G 3-4 toxicity Neutropenia Thombocytopenia Anemia GI toxicity X X X X X X X X Courtesy of Giuseppe Curigliano

27 When to consider for platinum in daily practice? Need for rapid loco-regional control -increased resectability Highest risk of relapse-stage III, very young patient Benefit to BRCA mutation carriers still under consideration Careful patient selection due to added risks of short term and long term toxicity DeMichele et al. SABCS 2015

28 Basal-like prognosis is particularly dependent upon responsiveness pcr do well, regardless of subtype Non-pCR do not do well, especially if triple negative Liedtke, C. et al. J Clin Oncol; 26:

29 Capecitabine in non-pcr HER2- Toi et al. NEJM 2017

30 Capecitabine

31 Outline Preferred chemotherapy regimen Platinum Capecitabine in non-pcr Practical issues -impact of delaying adjuvant CT in TNBC -small tumor -TIL

32 Chavez-MacGregor et al. JAMA Oncol 2016 Impact of delaying adjuvant CT in TNBC Gagliato et al. JCO 2014 Farolfi et al. EJC 2015 Breast cancer subtype Hormone receptor positive 1 ERBB ( ) TNBC 0.72 ( ) Unknown 1.02 ( )

33 2016 SABCS

34 Prognostic value of TIL. DFS for all patients (A) and in ER+/HER2 (B) ER /HER2 (C) HER2+ (d). M. V. Dieci et al. Ann Oncol 2015;annonc.mdv239

35 Prognostic value of stromal tumor-infiltrating lymphocytes (stils) in triple-negative breast cancer. Sylvia Adams et al. JCO 2014;32: by American Society of Clinical Oncology

36 Ongoing clinical trials immune checkpoints (IO) Phase NCT ID & number Defined condition of breast Cancer subtype IO monotherapy setting stage Experimental Drugs Control Primary endpoint III SWOG1418 (NCT ) Residual TNBC (ypt> 1cm or ypn+) Adjuvant after NAC Pembrolizumab for 1 year Observation as per guideline III NCT High risk TNBC Adjuvant or post-nac Avelumab for 1 year Observation as per guideline IO-based combination II I-SPY 2 (NCT ) * Neoadjuvant, personalized adaptive trial with novel agents Locally advanced breast cancer including TNBC and HR+HER2- BC Neoadjuvant II, III - Pembrolizumab+paclitaxel - Followed by doxorubicin + cyclophosphosphamide Standard NAC Invasive DFS (IDFS) - Overall DFS - DFS in PD-L1(+) patients pcr : 62.4% vs 22.3% IB III KEYNOTE-173 (NCT ) KEYNOTE-522 (NCT ) Locally advanced TNBC Neoadjuvant II, III (Arm A) : Pembrolizumab Pembrolizumab +nabpaclitaxel (Arm B) : Arm A+ Carboplatin Followed by ddac TNBC Neo/adjuvant - Neoadjuvant : Pembrolizumab + wpaclitaxel + Carboplatin (4C) Pembrolizumab + AC (4C) - Adjuvant : Pembrolizumab (9C) I/II NCT TNBC Neoadjuvant I-III - Durvalumab + nab-paclitaxel for 12 weeks - Followed by ddac II III Triple-Negative First-Line Study (NCT ) NeoTRIPaPDL1 (NCT ) TNBC (Neo)adjuvant - Neo : Atezolizumab + nab paclitaxel (4C) - Adj : Atezolizumab alone (4C) Locally advanced TNBC NA pcr (Arm A vs B) : 60% vs 90% placebo rather than pembrolizuma b Neoadjuvant Atezolizumab + nab-paclitaxel + carboplatin Nab-paclitaxel + carboplatin NA NA pcr, EFS pcr pcr EFS Ib NCT TNBC Adjuvant II/III - Peptide vaccine PVX-410 (6 infusion) + Durvalumab (2C) - After standard adjuvant chemotherapy NA DLT rate of PVX-410 in combination with durvalumab

37 Neo/Adjuvant ongoing trials in BRCA+

38 Conclusion Current standard treatment for early TNBC remains the chemotherapeutic approaches - Anthracycline+ alkylator+ taxane-based chemotherapy backbone for all patients. - Sequential strategy, dose-dense preferred Consider platinum drugs if patient has known BRCA1/BRCA2 germline mutation. Consider neoadjuvant approach to tailor use of adjuvant therapy with capecitabine on the basis of residual disease burden at surgical excision. Exceptions made for: extremely small cancers, ineligible patients.