Neoadjuvant Therapy for Triple Negative Breast Cancer Steven J. Isakoff, MD, PhD Dana-Farber Harvard Cancer Center/ Massachusetts General Hospital Cancer Center August 19, 2017 sisakoff@partners.org

TNBC Case What would you recommend for treatment? 46 year-old premenopausal woman Presents with new palpable mass in R breast Diagnostic mammogram: At the 11:00 position, 3 cm from the nipple, a 4.1 x 2.1 x 2.2 cm mass with irregular borders was seen Ultrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI present Bilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal. Genetic testing sent, BRCA1/2 negative What would you recommend for treatment?

What is the role of neoadjuvant therapy in TNBC? Old view: For inoperable or locally advanced cancers to convert to operable No proven benefit in long term outcome over adjuvant Modern View: Preferred Standard of Care for stage 2/3 Improve breast conservation rates and reduce extent of breast surgery Reduce extent of axillary surgery May allow risk stratification to guide adjuvant therapy selection Novel therapy development Provide prognostic information as surrogate for disease free survival Future role?: Allow risk stratification and de-escalation of therapy

Association of pCR with Event Free Survival in Triple Negative Breast Cancer FDA Meta-analysis Cortazar SABCS 2012

Ongoing Controversy: Platinum Agents What is the role of platinum in neoadjuvant therapy for TNBC in 2017?

Cisplatin and Breast Cancer Sledge reported 47% response rate in first line metastatic disease unselected for subtype RR range 42-54% in older studies in first line therapy RR 0-9% in previously treated unselected patients Renewed interest in patients with triple negative breast cancer Association of TNBC and BRCA1 7

Platinum for Neoadjuvant Therapy in Sporadic TNBC and BRCA1 Mutation Carriers > 2cm, Stage II/ III Research Core Biopsy N=28 Cisplatin 75mg/m2 q3wks x 4 cycles Assess Response Standard Adjuvant Therapy per MD pCR 22% Garber et al, SABCS 2006; Silver et al, JCO 2010

ALLIANCE/CALGB 40603 Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer N=443 ER/PR/HER2- Stage II-IIIB Sikov J Clin Oncol 2015. 33:13-21

Carboplatin improves pCR ALLIANCE/CALGB 40603 Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer Carboplatin improves pCR Sikov J Clin Oncol 2015. 33:13-21

CALGB 40603 – Event –free survival for carboplatin

GeparSixto Trial: Neoadjuvant carboplatin for Triple Negative Breast Cancer 315 pts (~53% TNBC) 40% node pos

GeparSixto: Carboplatin improves pCR for Triple Negative Breast Cancer

pCR Rates by germline BRCA status and Carboplatin in TNBC OR 0.94 (0.29-3.05) P= 0.92 OR 2.14 (1.28-3.58) P=.004 66.7% 65.4% 55.0% 36.4% gBRCA are highly sensitive to chemotherapy Platinum does not add benefit to gBRCA pCR Von Minckwitz, Lancet Oncology, 2014; Hahnen, JAMA Onc, 2017

Disease-free Survival: Effect of Carboplatin in TNBC Median DFS Follow-up = 35 months von Minckwitz et al. SABCS 2015

TILs in TNBC associate with improved pCR with platinum in GeparSixto Denkert C, JCO 2015

Role of Platinum in Neoadjuvant TNBC

TBCRC 030: Neoadjuvant Cisplatin vs Paclitaxel in TNBC >1.5 cm Cisplatin 75 mg/m2 q 3 wk x 4 Paclitaxel 80 mg/m2 q wk x 12 Tissue Collection Surgery Complete Adjuvant Chemotherapy Stratification LN + vs – T1/2 vs T3/4 Primary objectives: Compare pCR in platinum cohort with and without Homologous Recombination Deficiency (HRD high score or BRCA1/2+) Compare pCR in paclitaxel cohort with and without Homologous Recombination Deficiency PI: Erica Mayer, DFCI

Is cisplatin better than AC for preoperative therapy for BRCA carriers? Randomized Phase II trial: Neoadjuvant Cisplatin vs AC in Women with Germline BRCA Mutations N. Tung, PI

Schema: INFORM trial N=85 Eligibility: BRCA1/2 + HER2-neg T> 1.5 cm Research biopsy Cisplatin 75 mg/m2 x 4 AC x 4 dd or q 21 days Surgery Adjuvant Chemo N=85 N=170 (90 enrolled) Multicenter study Primary aims: pCR and Residual Cancer Burden (designed to show 20% improvement with cisplatin over AC) Secondary aim: biomarkers of response

Does platinum improve long term outcome: Adjuvant Platinum Therapy

Should Platinum be Standard for Neoadjuvant Tx for TNBC? My View: No, not routinely, not yet….. No threshold margin of improved pCR is associated with improved outcomes. Studies are underpowered for Event Free Survival and Overall Survival with inconsistent results Addition of carboplatin significantly increases toxicities and cost Need to better identify biomarkers to predict platinum sensitive disease (such as molecular subtype, Homologous Recombination Deficiency Assay – TBCBC030) Definitive Phase 3 trial is needed – NRG BR003 comparing standard adjuvant chemotherapy +/- carboplatin Standard combination chemotherapy remains the standard of care In selected cases, adding platinum is reasonable for improved local control

Can we use pCR/RCB in TNBC to reduce treatment? HYPOTHETICAL TRIAL Carboplatin/ taxane Surgery x 4-6 cycles No pCR/ RCB 2/3 Yes pCR/ RCB 0/1 Adriamycin/cytoxan x 4 No further therapy Hypothetical design: Non-inferiority trial HR boundary 1.15

Prospective Registry Study of AC-T and Taxotere/Carbo x 6 and impact of pCR Carboplatin/Docetaxel pathological response by gBRCA status Comparison of Carboplatin/Docetaxel and ACT pCR# All Patients (n=49) BRCA1/2 Wild type (n=36) BRCA Mutation (n=13) pCR; n(%) 32 (65%) 22 (61%) 10 (77%) p=0.50 RCB 0/1; n(%) 38 (78%) 27 (75%) 11 (85%) p=0.70 p=0.036* p=0.038* Sharma, ASCO 2016

Management of Residual Disease After Neoadjuvant Therapy Masuda et al. NEJM 2017; Lee, Toi et al. SABCS 2015

CREATE-X: Adjuvant Capecitabine for non-pCR Masuda et al. NEJM 2017; Lee, Toi et al. SABCS 2015

Management of Residual Disease After Neoadjuvant Therapy The US NCI felt the data from CreateX was so compelling it mandated a change in the design of Ecog1131 which was evaluating use of adjuvant platinum with residual disease to make capecitabine the comparator.

Novel therapies for neoadjuvant TNBC

I-SPY 2 TRIAL Schema: HER2- Signatures Immunotherapy in Pre-operative breast cancer I-SPY 2 TRIAL Schema: HER2- Signatures Presented By Rita Nanda at 2017 ASCO Annual Meeting

Immunotherapy in Pre-operative breast cancer Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Presented By Rita Nanda at 2017 ASCO Annual Meeting

Immunotherapy in Pre-operative breast cancer Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Pembrolizumab graduated to phase 3 – the Keynote 522 study Presented By Rita Nanda at 2017 ASCO Annual Meeting

The future: Targeting the Heterogeneity of TNBC

Heterogeneity in response to neoadjuvant chemotherapy Masuda et al Clin Cancer Res; 19(19) October 1, 2013

Potentially Actionable Mutations in post-Neoadjuvant Chemotherapy with residual disease Balko, Cancer Discovery 2014;4:232-245

Neoadjuvant Therapy with Ipatasertib (AKT inhibitor) with paclitaxel Schema: LOTUS study Taxol weekly + Ipatasertib 400mg QD (3wk on/1wk off) R 1L mTNBC STRATIFY:Adjuvant or neoadj (y/n), PTEN status (null vs h-score 1 to 150 vs >150) n = 120 Taxol weekly + Placebo Primary endpoint: PFS in ITT and PFS in PTEN low Secondary endpoint: PFS in Dx+ (PTEN loss + PIK3CA mutants), OS, ORR PI3K/AKT/PTEN Altered by NGS Kim, Lancet Oncology 2017

Neoadjuvant Therapy with Ipatasertib (AKT inhibitor) with paclitaxel Schema: FAIRLANE Study Surgery Taxol weekly + Ipatasertib 400mg QD (3wk on/1wk off) x 12 wks Neoadjuvant T>1.5 cm R STRATIFY:PTEN status (null vs h-score 1 to 150 vs >150), node, size n = 150 Taxol weekly + Placebo x 12 wks Primary endpoint: pCR in ITT and PTEN low Secondary endpoint: pCR in PTEN low/PIK3CA/AKT altered FAIRLANE Completed Accrual Summer 2017 Results to be presented ASCO 2018 Phase 3 study underway in 1st metastatic TNBC (and ER+)

Summary and Take-Home Points Platinum agents can increase pCR rates with neoadjuvant therapy: But, long term benefit remains inconsistent and controversial Significantly increases toxicity In the absence of more data, should not be routinely used in the neoadjuvant setting, but in select cases may be reasonable. Capecitabine may have a role after neoadjuvant therapy with significant residual disease Exciting preliminary results with neoadjuvant immunotherapy added to chemotherapy, now being tested in phase 3 studies. Molecular sub-classification may lead to targeted novel agents in TNBC. Finally, given the lack of preferred therapies, clinical trial participation should always be considered.

TNBC Case What would you recommend for treatment? 46 year-old premenopausal woman Presents with new palpable mass in R breast Diagnostic mammogram: At the 11:00 position, 3 cm from the nipple, a 4.1 x 2.1 x 2.2 cm mass with irregular borders was seen Ultrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI present Bilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal. Genetic testing sent, BRCA1/2 negative What would you recommend for treatment? My recommendation: If no clinical trial, standard neoadjuvant therapy with AC-T, with possible adjuvant capecitabine if significant residual disease

Thank you sisakoff@mgh.harvard.edu Acknowledgments Eric Winer Nadine Tung Erica Mayer Laura Spring