SABCS 2016: Medical Oncology

1/27/17 SABCS 2016: Medical Oncology Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education University of California San Francisco Comprehensive Cancer Center Topics What did we learn about extending adjuvant hormone therapy? Can genomic tests help predict late recurrence? Updates on hormone therapy for advanced disease What s new in HER2 positive disease? Chemotherapy topics Anthracyclines in adjuvant therapy Novel immunotoxin Tumor infiltrating lymphocytes Supportive care AI arthralgias Hair loss 1

Risk of Late Recurrence in ER+ Disease Early-stage (I/II) ER+ patients have good overall prognosis, but >50% of recurrences occur after Year 5 Clinical features affect recurrence risk in TransATAC Endocrine Therapy 1. EBCTCG. Lancet 2005;365:1687-71. 2. Saphner T, et al. J Clin Oncol 1996;14:2738-4. Natural History of HR+ ESBC: EBCTCG 91 trials, 46,000 women with 5 years endocrine therapy for ESBC Results: risk of distant recurrence year 5-20 T1N0: 14% T2N0: 21%, T2N1-3: 29%, T2N4-9: 47% Other risk factors: tumor grade, Ki67 Implications: Clinicopathologic factors help to identify those at higher risk of recurrence after 5 years of endocrine therapy Role of extended adjuvant therapy: MA17R, NSABP B42 Role of genomics as predictive markers? Pan et al, ASCO 2016 2

Risk of Late Recurrence in ER+ Disease Clinical and pathologic factors are prognostic 5-10y DR 5-15y DR 5-20y DR T + N T1N0 4% 9% 14% T2N0 8% 14% 21% T1N1 8% 15% 23% T1N2 15% 30% 41% T2N1 12% 20% 29% T2N2 20% 35% 47% T+N+G T1N0G1 2% 7% 11% T1N0G2 4% 9% 14% T1N0G3 5% 13% 20% 1. EBCTCG. Lancet 2005;365:1687-71. 2. Saphner T, et al. J Clin Oncol 1996;14:2738-4. 3. Pan H et al., J Clin Oncol 34, 2016 (suppl; abstr 505) Can we Improve Long-Term Outcome for HR+ ESBC? Generally, AIs for 5 years are better than tamoxifen for 5 years (EBCTCG 2015: improved all cause mortality with AIs) Sequencing tamoxifen and an AI is an alternative to 5 years of an AI Prolonging tamoxifen after tamoxifen may be beneficial, depending on individual risk Adding 5 years of an AI after 5 years of tamoxifen is beneficial 3

Extended Endocrine Therapy Randomized Trials: Tamoxifen followed by AI Trial Duration of Therapy (y) N Median Followup (y) Diseasefree Survival 1 Absolute Benefit Hazard Ratio (95% CI) NNT (All) 2 NNT (DR) 3 MA.17 TAM x 5y Placebo x 5y TAM x 5y AI x 5y 2587 2583 2.5 89.8% 94.4% 4.6% 0.58 (0.45-0.76) P<0.001 41 86 NSABP B-33 TAM x 5y Placebo x 5y TAM x 5y AI x 5y 779 783 2.5 89% 91% 2% RR: 0.68 P=0.07 39 156 ABCSG 6A TAM x 5y Placebo x 3y TAM x 5y AI x 3y 469 387 5.2 88.2% 92.9% 4.7% 0.62 (0.40-0.96) P=0.031 23 29 ATLAS TAM x 5y No further Rx TAM x 5y TAM x 5y 3418 3428 7.6 74.9% 78.6% 3.7% RR 0.84 (0.76-0.94) p=0.002 36 98 attom TAM x 5y No further Rx TAM x 5y TAM x 5y 3485 3468 10 68% 72% 4% RR 0.85 (0.76-0.95) P=0.003 38 NR MA.17R TAM x 0-5y + AI x 5y Placebo TAM x 0-5y + AI x 5y AI x 5y 959 959 6.3 91% 95% 4% 0.66 (0.48-0.91) P=0.01 31 87 1. Based on disease-free survival or cumulative risk of recurrence rates as reported in the primary publications (note that the definitions of disease-free were not identical across trials) 2. Number needed to treat (NNT) based on all recurrences (local, regional, and distant) and contralateral events 3. Number needed to treat (NNT) based on distant recurrences (DR) only SABCS 2016: NSABP B-42, DATA, IDEAL 1. Goss PE et al, J Natl Cancer Inst 2005;97:1262 71. 2. Mamounas EP et al., J Clin Oncol 2008;26:1965-1971. 3. Jakesz et al., J Natl Cancer Inst. 2007 Dec 19;99(24):1845-53. 4. Davies C et al., Lancet. 2013 ;381(9869):805-16. 5. Gray et al., J Clin Oncol 31, 2013 (suppl; abstr 5). 6. Goss PE et al., N Engl J Med. 2016 Jun 5 (Online) MA.17R: Extending Adjuvant Letrozole for 5 Years after Completing either: 5 years of AI alone OR 5 years Tamoxifen followed by 5 years AI Total of 1918 patients, median FU 6.3 years Median age 65, median time from diagnosis 10 years 46% node negative 5 year DFS: 95% LET vs 91% PLAC HR DFS 0.66, P=0.01 Letrozole Placebo DFS events: Distant: 42 vs 53 (11 events) LRR: 19 vs 30 (11 events) Bone: 28 vs 37 New CL breast cancer: 13 vs 31 Fractures: 14 vs 9% New onset osteoporosis: 11 vs 6% Contralateral new breast cancers Placebo Letrozole HR 0.42 P = 0.007 Goss et al, NEJM 2016 4

NSABP B-42: Schema Postmenopausal Pts with ER+ or PR+ Breast Cancer Stage I, II, or IIIa invasive BC at diagnosis Disease-free After 5 Years of Endocrine Therapy AI X 5 yrs or TAM X < 3 yrs à AI to Complete 5 yrs Stratification: Pathological nodal status (Negative, Positive) Prior adjuvant TAM (Yes, No) Lowest BMD T score: spine, hip, femur (>-2.0, -2.0 SD) Letrozole X 5 yrs R Placebo X 5 yrs Primary endpoint: DFS, CL BC, 2nd non-breast Ca, death from any cause 1. Mamounas EP et al. San Antonio Breast Cancer Symposium, 2016 Mamounas et al, SABCS 2016 NSABP B-42: Results 3966 pts were randomized from 9/06-1/10 Median FU for efficacy analyses: 6.9 years Compliance: Only 62.5% of P patients and 60.3% of L patients completed all 5 years of therapy 1. Mamounas EP et al. San Antonio Breast Cancer Symposium, 2016 *P-value did not reach statistical significance level of 0.0418 5

NSABP B-42: Additional Analyses Cumulative Incidence of BCFI Event No difference in OS 92.3 (P) vs 91.8% (L); HR 1.15 (p=.22) Cumulative Incidence of Distant Recurrence Toxicity No difference in osteoporotic fractures 4.8 vs 5.4% (p=.27) Increase in arterial thrombotic events 3.4 vs 4% P=0.007 1. Mamounas EP et al. San Antonio Breast Cancer Symposium, 2016 NSABP B-42 and NCIC MA.17R Comparison of HRs for Various Endpoints Trial B-42 1 (n=3,923 631 events) MA.17R 2 (n=1,918 165 events) Endpoint Effect DFS BCFI DR OS HR 0.85* 0.71 0.72 1.15 P-value 0.048 0.003 0.03 0.22 HR 0.80*** 0.66** NR 0.97 P-value 0.06 0.01 NR 0.83 * DFS (Recurrence + CBC + non-breast CA + deaths as first events) ** Selected as DFS in MA.17R (Recurrence + CBC) *** DFS (Recurrence + CBC + Deaths from any cause) 1. Mamounas EP et al. San Antonio Breast Cancer Symposium, 2016. 2. Goss P. et al: NEJM 2016 6

Phase III DATA Trial: 3 vs 6 Years of Anastrozole after 2-3 Years of Tamoxifen ü ü ü ü ü Postmenopausal at randomization ER+ and/or PR+ No sign of disease recurrence M0 breast cancer After 2-3 years adjuvant tamoxifen Stratification Nodal status ER/PR status HER2 status Tamoxifen duration 3 years anastrozole 1 mg daily 6 years anastrozole 1 mg daily Primary endpoint Adapted DFS (adfs): DFS >3 years after randomization 1912 patients randomized: minimum FU >6 years 1660 included in ITT (194 had DFS events within 3 years) 66-68% node positive, 81-81% grade II-III, 54-56% >T2 N=1660 3-year adfs: 90.7% vs. 88.9% 6-year Anastrozole (N=827) 3-year Anastrozole (N=833) 5-year adfs (%) 83.1 79.4 HR (95% CI) 0.79 (0.62 1.02) P-value 0.07 Tjan-Heijnen et al, SABCS 2016 DATA: Additional Analyses adfs if ER+ and PR+, HER2-, pn+, Chemo+ No difference in adapted OS (4.1 yrs FU) 90.8 vs 90.4% Compliance Early termination for AEs, refusal and other 30.6% vs 17.8% N=597 5-year adfs (%) 6-year Anastrozole (N=293) 3-year Anastrozole (N=286) 86.0 75.9 P value (HR, 95% CI) 0.01 (0.58;.39-.89) Toxicity: no real difference Grade, years 0-6 6-year Anastrozole 3-year Anastrozole (N=827) (N=833) Any Grade 3 Any Grade 3 Arthralgia / myalgia 57.6% 8.0% 51.9% 5.5% Bone fractures 9.8% 2.1% 7.4% 2.5% Osteopenia / osteoporosis 20.9% 1.3% 16.5% 0.8% Cardiovascular incl. arrhythmia 13.4% 3.5% 12.9% 3.4% 7

Phase III IDEAL Trial: Optimal Duration of Letrozole after 5 Years Tamoxifen Aromatase Inhibitor (AI) R Letrozole Primary endpoint: DFS 1824 patients Median FU 6.5 yrs 74% N+ Tamoxifen AI Letrozole 5 years adjuvant therapy Postmenopausal ER/PR positive No recurrence / 2 nd malignancy 0-2 years 2.5 or 5 years extended therapy Stratification: Prior endocrine therapy, time after endocrine therapy, nodal status, adjuvant chemotherapy No difference in DFS Primary: 88.4 (2.5 yr) vs 87.9% (5 yr); HR 0.96 Subgroup analysis Suggested benefit in node positive, but 2.5 yrs >5 for N neg, low grade No difference in OS 2.5 vs 5 years Primary: 93.5 vs 92.6% No diference in DMFI 6.1 vs 7.1% van de Velde (Blok) et al, SABCS 2016 Additional Analyses Toxicity 2.5 years 5 years N pa,ents 640 (70%) 643 (70%) N AE 1591 1843 ( 16%) % CTC grade 3-4 9.8% 9.7% HR: 0.37 (0.18-0.77) P-value 0.008 2 nd BC 5 years 2.5y: 1.9% 5y: 0.9% Arthalgia: 14% Hot flashes:12% Osteoporosis: 10% Compliance: early stopping without PD 2.5 years 5 years Early stop (n) 241 (27%) 385 (~42%) Symptoms/AE + refusal 179 (74%) 254 (66%) 8

Can Genomic Tests Help to Predict Late Recurrence Risk? Comparison of Prognostic Signatures for Breast Cancer Recurrence in TransATAC (n=818) Signature Information included Clinical Treatment Score (CTS) Nodal status, grade, tumour size, age, treatment Immunohistochemical markers (IHC4) ER, PgR, Ki67, HER2 Oncotype Recurrence Score (RS) 21 genes (oestrogen, proliferation, invasion, HER2 genes) Breast Cancer Index (BCI) H/I and 5 proliferation genes (Molecular Grade Index) Prosigna (ROR) EndoPredict (EPclin) 46 genes, proliferation score, tumour size (EU cut-offs from transatac for N- and N+) 12 genes (proliferation, differentiation, oestrogen); nodal status and tumour size 5 years tam or AI, NO chemo, primary endpoint DR Sestak et al, SABCS 2016 9

N0 N+ Late Distant Relapse by Assay, transatac (yr 5 to10) IHC4 BCI RS ROR EPclin IHC4 BCI RS ROR EPclin CTS 16.6 16.6 16.6 16.6 16.6 16.0 Sestak SABCS16 3.3 1.9 11.2 10.3 18.4 Likelihood Ratio χ 2 CTS 16.0 16.0 16.0 16.0 1.2 1.8 1.1 4.1 4.4 Likelihood Ratio χ 2 % Improvement 20.0% 67.5% 11.4% 111.0% 62.0% % Improvement 7.5% 11.3% 6.9% 25.6% 27.5% Distant recurrence free (%) Distant recurrence free (%) 80 90 100 80 90 100 80 90 100 80 90 100 60 80 100 60 80 100 60 80 100 60 80 100 BCI RS ROR EPclin RS ROR EPclin 5 6 7 8 9 10 Follow-up time [years] DR risk % 2.5% 14.4% 15.9% 1.4% 10.0% 23.2% 4.3% 14.6% 5 6 7 8 9 10 Follow-up time [years] DR risk % BCI Patients % in risk groups 63.6% patients 23.6% patients 12.9% patients 4.8% 65.6% patients 9.6% 25.1% patients 16.1% 9.4% patients 14.3% 19.7% 36.5% 0% 13.0% 25.0% 3.3% 23.6% 54.6% patients 30.8% patients 14.6% patients 73.5% patients 26.5% patients Patients % in risk groups 51.7% patients 32.4% patients 15.9% patients 17.9% 61.0% patients 19.5% 30.2% patients 27.5% 8.8% patients 8.2% patients 28.0% patients 63.7% patients 22.0% patients 78.0% patients Clinicopathologic Factors are Critical with Genomic Testing to Assess Late Recurrence Risk A new BCI Prognostic algorithm was developed to assess risk of recurrence in HR+ patients with 1-3 positive nodes (BCIN+) New model developed using TransATAC N1 patients (n=209) Independent validation in retrospective case series (N=402) BCIN+ categorized 20% of patients as Low Risk 1.3% risk of recurrence over 15 years Distant Recurrence (%) 0 10 20 30 40 50 All Patients (0-15 Yr) Low High HR: 25.93 (3.61-186.22) P < 0.0001 29% 1.3% 0 3 6 9 12 15 Years No. at risk Low 81 81 81 73 46 21 High 321 291 264 214 118 60 Distant Recurrence (%) 0 10 20 30 40 50 HR: NA P < 0.0001 HER2- (0-15 Yr) Low High 29.1% 0% 0 3 6 9 12 15 Years No. at risk Low 57 57 57 50 25 4 High 202 184 166 134 61 17 Distant Recurrence (%) 0 10 20 30 40 50 All Patients (5-15 Yr) Low High HR: 12.39 (1.7-90.35) P = 0.0014 16.1% 1.3% 5 7 9 11 13 15 Years No. at risk Low 81 80 73 53 34 21 High 268 255 214 147 97 60 Distant Recurrence (%) 0 10 20 30 40 50 HR: NA P = 0.0037 HER2- (5-15 Yr) Low High 5 7 9 11 13 15 Years No. at risk Low 57 56 50 32 14 4 High 169 160 134 83 46 17 Zhang et al. ASCO 2016 17% 0% 10

Summary and Analysis Variation in study designs makes comparisons difficult Relatively low risk of recurrence at median FU Careful assessment of potential risks and benefits is required before recommending extended AI Rx Patients randomized on extended duration trials Are unique as tolerated 2-5 years of AI therapy Early discontinuation for toxicity frequent; impacts ability to analyze impact of therapy Patients at very high risk for late recurrence should be considered for extended duration hormone therapy Optimal duration unknown; AI or tamoxifen reasonable, awareness of toxicities critical Genomic tests to assess risk and predict benefit are critical Stay tuned to further analyses from NAABP B-42 Role of targeted agents, CDKi and others, remains to be determined Expected Survival Impacts Potential Benefits of Extended Adjuvant Therapy Any (T1/2, N0-9) ER+ disease, adjusted for T and N status Age after 5 years ET Distant recurrence: Adjusted RR (95% CI) Survival, years 5-20, if no breast cancer death <40 1.4 (1.1-1.8) 97% 40-49 0.9 (0.8-1.0) 93% 50-59 0.9 (0.8-0.9) 91% 60-69 1.0 79% 70-79 1.1 (1.0-1.2) 48% 1.0 1.5 Pan et al, ASCO 2016 11

Effect of Body Mass Index on Recurrence in ATAC Trial BWEL Study Schema 3136 participants Key Eligibility: Stage II-III breast cancer HER-2 - BMI 27 kg/m2 R A N D O M I Z E 2-year telephone-based weight loss intervention + Health education Health Education Alone Conducted through NCTN/NCORP Activation date: August 1, 2016 J Clin Oncol 2010; 28; 3411-3415 Study design Recent Phase III First-Line Studies in HR+ MBC Paloma-2 Finn et al, NEJM 2016 Letrozole/Pla vs Letrozole/Palbociclib No. of pts 666 No progression on AIs PFS 14.5 vs 24.8 mo HR 0.58 (0.46-0.72) p<0.000001 Monaleesa-2 Hortobagyi et al, NEJM 2016 Letrozole/Pla vs Letrozole/Ribociclib 668 No progression on AIs 14.7 vs NR (19.9-NR) mo HR 0.556 (0.43-0.72); p=0.00000329 All oral Yes Yes No Subset difference Falcon Robertson et al, Lancet 2016 Anastrozole/Pla vs Fulvestrant/Pla 462 No prior hormone therapy 13.8 vs 16.6 mo. HR 0.797 (0.64-0.999); p=0.0486 No No 13.8 v 22.3 mo in n= 218 (47%) without visceral disease No difference in those with visceral disease 12

Comparison of Trials in Patients with Progression on Prior NSAI Study design PALOMA 3 Turner et al, NEJM 2015, SABCS 2016 Fulvestrant/pla vs fulvestrant/palbociclib BOLERO 2 Baselga et al, NEJM 2012 Yardley et al, Adv Ther 2013 Exemestane/pla vs exemestane/eve Patient # 521 724 131 PFS (mo) p value (HR) 4.6 vs 11.2 p<.0001, (HR 0.5) 3.2 vs 7.8 (inv) 4.1 vs 11 (central) p<.0001 (HR.38) PreCOG Kornblum et al, SABCS 2016 Fulvestrant/pla vs fulvestrant/eve 5.1 vs 10.4 p=.02 (HR.6) Abemaciclib Single agent ORR 19.7% (Dickler et al, ASCO 2016) Crosses BBB, diarrhea > neutropenia NeoMONARCH (Hurvitz et al, SABCS 2016) 223 pts, biomarker trial Complete cell cycle arrest at 2 wks Induces immune infiltrate Response Rate (%) Complete Cell Cycle Arrest 100 8.2 (3.4, 20.2) OR = p<0.001 b 80 11.2 (4.7, 27.4) p<0.001 b 60 40 66.1 58.8 20 0 14.8 8 37 30 Responders : (Ki67 index <2.7% at 2 weeks) BELLE-3: Buparlisib/Fulvestrant after mtori PFS by PIK3CA Status Probability of PFS, % 100 Tissue (mutant) Buparlisib + Placebo + Fulvestrant Fulvestrant 80 80 Primary tumor Median PFS, 4.7 1.4 Median PFS, 2.8 2.7 tissue (PCR) months (95% CI) (2.9 6.7) (1.4 2.2) months (95% CI) (2.0 3.7) (1.4 2.9) 60 60 N=321 HR (95% CI) 0.39 (0.23 0.65); p<0.001 HR (95% CI) 0.83 (0.60 1.14); p=0.117 40 40 PIK3CA mutant: Significant hepatic toxicity, hyperglycemia, rash, 34% depression/anxiety 20 20 Future 0 development of pan PI3K 0 inhibitors not feasible 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 22 24 26 but biomarker data intriguing Alpha 100 specific PI3K hold signficiant 100 Buparlisib + Placebo + ctdna (mutant) Buparlisib + Placebo + promise ctdna (WT) Fulvestrant Fulvestrant Fulvestrant Fulvestrant Alpelsib 80 (Solar-1) 80 Median PFS, 4.2 1.6 Median PFS, 3.9 2.7 months (95% CI) (2.8 6.7) (1.4 2.8) months (95% CI) (2.8 4.3) (1.5 3.6) Pictilisib 60 (Sandpiper) 60 HR (95% CI) 0.46 (0.29 0.73); p<0.001 HR (95% CI) 0.73 (0.53 1.00); p=0.026 Triplet 40 therapy of interest (hormone 40 rx, PI3Ki, CDKi) ctdna samples at study entry (BEAMing) N=348 PIK3CA mutant: 39% Probability of PFS, % 20 Mutant 100 20 Wild-type Tissue (WT) Buparlisib + Placebo + Fulvestrant Fulvestrant 0 0 PCR, polymerase chain reaction; WT, wild-type. p-values are one-sided. 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, Months 26 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, Months DiLeo et al, SABCS 2016 13

Optimal Sequencing of Endocrine Therapy in ER+ MBC 1 st line approach Delay Start of Chemotherapy OS 2 nd line approach A. Conventional endocrine mono-therapy B. Optimally selected endocrine mono-therapy AI alone 8 14 months Fulvestrant 500 22 months Exemestane 3 4 months (ie. endo Rx naïve, non-visceral mets, biomarker) AI or fulvestrant + everolimus 7.8-11 months Fulvestrant + CDK4/6 I 11.2 months AI + CDK4/6 i 7 9 months? AI + everolimus 7 9 months? A B C 2 nd line post Fulvestrant: responsive to 2 nd line combinations? C. Combination Endocrine Strategy AI + CDK4/6 i 24 months Fulvestrant 500 6.5 months? PI3K inhibitors? AI + everolimus 7 11 months? 2 nd Line post CDK 4/6 inhibitors: still endocrine responsive and to what therapy? 0 5 10 15 20 25 30 35 Cumulative Median Progression-Free Survival (PFS) in months Overall Survival (OS) Adapted from Johnston, SABCS 2016 Symptom Control is a Critical Issue: Managing Arthralgias Exercise, yoga, acupressure, acupuncture. NSAIDS Regular check in with clinic/providers Duloxetine HCL (SWOG S1202: Henry et al, SABCS 2016) SNRI, FDA approved for chronic pain disorders Post menopausal, stage I-III, AI for 3 weeks 36 months Average MS pain of >4/10 on AI Average joint pain decrease in both arms The difference between the 2 arms started at 2 weeks Difference in average joint pain 0.82 (p=0.002) Side effects manageable Percentage of pa6ents with 2 point improvement 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 54% 44% 69% 69% 49% Duloxe6ne Placebo 60% 60% 59% 2 weeks 6 weeks 12 weeks 24 weeks 14

Preventing Chemotherapy Induced Alopecia (in press, JAMA 2017) SCALP (Paxman, Nangia et al, SABCS 2016) 140 pts with stage I-II breast cancer 1/3 anthracycline. 2/3 taxane Stopped at interim analysis Dignicap (Rugo et al, ASCO 2015) Taxane based chemotherapy Success by regimen TC (63.2%), Tca (83.3%), paclitaxel (100%) Dean Score N (%) DigniCap N = 101 Success/ Failure % (N) 0 (no hair loss) 1 (>0 and up to 25% hair loss) 5 (5%) 31 (30.7%) Success: 66.3%* (71, 2 (>25% and up to 50% 31 95% CI, 56.3- hair loss) (30.7%) 75.4%) 3 (>50% and up to 75% 19 hair loss) (18.8%) Failure: 4 (> 75% hair loss) 15 33.7% (34) (14.9%) Control N = 16 Success/ N (%) Failure % (N) 0 (0.0%) 0 (0.0%) 0 (0.0%) Success: 0.0% (0) 1 (6.3%) Failure: 100.0% 15 (16) (93.8%) *p-value for comparing DigniCap to control P<0.001 from Fisher s exact test HER2+/HR+ Disease NSABP B-52 (n=309) Neoadjuvant therapy HER2+/HR+ TCHP x 6 vs TCHP + estrogen deprivation No difference in pcr 41 vs 46% No difference in pre- or post-menop women No reason to add ET to chemo + HER2-targed rx in HER2+ disease PERTAIN (n=258) First-line ph II trial in HER2+/HR+ MBC TP/AI vs T/AI Allowed chemotherapy first PFS: 18.9 vs 15.8 mo HR 0.65, p.007 ORR: 63 vs 56%, NS Pertuzumab works, reasonable to continue when switching from THP to T/AI Rimawi et al, SABCS 2016 Rimawi et al presented by Arpino), SABCS 2016 15

N=150 HER2+ Breast Cancer stage I-IIIA Baseline PAM50 Predicting Benefit from HER2 Targeted Therapy: PAMELA Trial PAMELA trial schema 18 weeks Trastuzumab 6 mg/kg every 3 weeks Lapa6nib 1000 mg/day + Letrozole or Tamoxifen if HR+ Week 2 Week 6 PAM50 Ultrasound PD* Trastuzumab 6 mg/kg every 3 weeks Lapa6nib 750 mg/day Paclitaxel 80 mg/m 2 weekly x 12 *, defined as any increase in tumor size. This presentation is the intellectual property of the author/presenter. Contact them at alprat@clinic.cat for permission to reprint and/or distribute S U R G E R Y Adjuvant systemic treatment was at the discremon of the treamng physician Intrinsic subtype distribution at baseline LumA LumB HER2-E Basal-like Normal-like Intrinsic subtypes: heterogeneous in HER2+ disease (n=151) Vary by ER status HER2-E have greater pathway activation, better response to combination neoadjuvant therapy Do these patients need less? pcr rate 100% 80% 60% 40% 20% 0% 40.6% =30.6% 10.0% pcr breast pcr All samples N=151 5.9% 2% 66.9% 34.7% 14.6% =24.7% 10.6% 10.0% pcr breast/axilla 100% 80% 60% 40% 20% 0% HR+ samples N=77 LumA LumB HER2-E 49.3% 1.3% Basal-like Normal-like 40.6% HER2-E (n=101) 28.6% 20.8% 0% LumA (n=22) 12.5% LumB (n=16) 2.7% LumA 12.2% LumB HR-neg samples N=74 HER2-E Basal-like Normal-like pcr breast 11.1% 85.1% 66.7% Basal-like Normal-like (n=9) (n=3) Pratt et al, SABCS 2016 Chemotherapy for TNBC Update of the TNT trial (Tutt et al, SABCS 2016) TNBC, first line therapy, carboplatin vs docetaxel Carboplatin superior for ORR in gbrca BRCAness did not predict benefit from carboplatin (docetaxel better) TnAcity (Yardley et al, SABCS 2016) First line therapy for TNBC Nab-paclitaxel (125 mg/m2)/carbo AUC 2 less toxic nab/ca (n=64) nab/gem (n=61) Gem/Ca (n=66) ORR 72% 39% 44% mpfs 7.4 mo 5.4 mo (HR 0.6, 0.39-0.93, p.02) 6.0 mo (HR 0.61, 0.39-0.94, p.03) 16

Novel Agents: Sacituzumab Govitecan (IMMU-132) Anti-Trop-2 Antibody Drug Conjugate Phase I expansion in TNBC 10mg/kg days 1 and 8 q 21 Median number of prior therapies 5 (2-12) 85 evaluable patients ORR: 29.4% (25/85) 2 CR, 26 PR, 33 SD ; CBR 44% Median DOR 10.8 mo PFS 6 mo. Toxicity (>gr3) 39% neutropenia, 7% FN 10% emesis 13% diarrhea 10% hypophosphatemia Antibody-drug conjugate targeting Trop-2 Antigen present in many epithelial cancers, including TNBC Delivers SN-38, a topoisomerase I inhibitor Bardia et al, SABCS 2016 Role of Anthracyclines in ESBC: DBCG 07 DC x 6 vs EC x 3 D x 3 in TOP2A Normal BC Selection Criteria Invasive breast cancer Comorbidity index < 3 High risk 1. Node positive 2. High risk node neg. Young age ER negative HER2+ T size High grade Altered TOP2A TOP2A/Cen17 ratio < 0.8 or 2.0 5160 TOP2A tested 16% (835) altered TOP2A Normal TOP2A TOP2A/Cen17 ratio 0.8-1.9 3 x EC 3 x Docetaxel 90/600 mg/m 2 100 mg/m 2 3 x EC 90/600 mg/m 2 6 x DC 75/600 mg/m 2 N=835 3 x Docetaxel 100 mg/m 2 N=994 N=1006 ABC trials (Blum ASCO 2016) Benefit of anthracyclines greatest in higher risk disease (TN, node positive) Is removal of TOP2A mutant cancers important? (Anthracycline sensitive?) Seems reasonable to use DC in lower risk tumors still requiring adjuvant chemotherapy but do those patients need chemorx? EC/D not superior to DC in TOP2A normal BC and more toxic Ejlertson et al, SABCS 2016 17

Tumor Infiltrating Lymphocytes Metaanalysis of 3771 patients (GBG) High TILS are more frequent in TNBC (30%)>HER2 (19%)>luminal tumors (13%) TILS are linked to increased pcr rates in all subtypes High TILS associated with OS for TNBC and HER2; low TILS associated with OS for luminal TILS in the Cleopatra trial More common in ER neg, and Asian>White>AA Lower TILS in metastatic tumor than primary, and in all visceral sites but lung OS associated with mean TIL level Linear impact, each 10% increase in TILS=11% reduction in risk of death. Denkert et al, SABCS 2016; Luen et al, SABCS 2016 UCSF TBCRC Multi-Center Immunotherapy BCRF Funded Trial TNBC OX-40 and 4-1BB antibodies are immune agonists Binimetinib :MEK 1/2 inhibitor Avelumab: PD-L1 inhibitor 18

1/27/17 Raising the Bar in the Treatment of Breast Cancer Thank you! 19