PHEREXA: Survival Data Capecitabine (X) + trastuzumab (H) Eligibility HER2+ mBC Prior treatment with taxane Progression on 1st-line trastuzumab-based therapy R X + H + pertuzumab (P) H + X (n = 224 ) H + X + P (n = 228) Hazard ratio p-value Median PFS by IRF 9.0 mo 11.1 mo 0.82 0.07 Median OS (mo) 28.1 36.1 0.68 NE IRF = independent review facility; NE = not evaluable due to hierarchial testing of OS after the primary IRF PFS endpoint Urruticoechea A et al. Proc ASCO 2016;Abstract 504.

“In patients who have not been treated with pertuzumab and chemotherapy, it is reasonable to offer this treatment in the second-line setting.” Hope S Rugo, MD

HERITAGE: A Phase III Trial of Proposed Trastuzumab Biosimilar Myl-1401O in HER2+ mBC Myl-1401O + taxane (n = 230) Trastuzumab + taxane (n = 228) ORR at 24 weeks 69.6% 64.0% 95% CI (63.62, 75.51) (57.81, 70.26) Ratio of ORR: Myl-1401O/ trastuzumab (FDA) 1.09 Difference in ORR: Myl-1401O/trastuzumab (EMEA) 5.53 Results confirmed efficacy equivalence based on ratio of ORR and difference in ORR. No difference in median LVEF between the 2 study arms Similar immunogenicity was observed Rugo HS et al. Proc ASCO 2016;Abstract LBA503.

Use of Trastuzumab Biosimilar Myl-1401O in the Adjuvant Setting “I feel that based on this data and all of the similar physical and immunologic characteristics that it would be safe to use [Myl-1401O] as a substitute for trastuzumab.” Hope S Rugo, MD

Trials of Checkpoint Inhibitors in TNBC Phase IB KEYNOTE-012: Pembrolizumab in TNBC N = 27 women with PD-L1-positive tumors evaluable for response ORR = 18.5% Duration of response: Not yet reached Phase Ia study of atezolizumab in TNBC N = 21 women with PD-L1-positive tumors evaluable for response ORR = 19% Nanda R et al. J Clin Oncol 2016;34(21):2460-7; Emens LA et al. Proc AACR 2015;Abstract 6317.

Placebo q2wk + nab-paclitaxel IMpassion130: Phase III Randomized Trial of Atezolizumab with Nab-Paclitaxel for 1st-line Metastatic Triple-Negative Breast Cancer (mTNBC) Target Accrual: 900 (Active, recruiting) Eligibility Locally advanced, measurable TNBC or mTNBC No prior systemic therapy for advanced TNBC ECOG PS 0-1 No history of autoimmune disease Atezolizumab 840 mg q2wk + nab-paclitaxel (100 mg/m2, 3 wks on/1 off) x ≥6 R Placebo q2wk + nab-paclitaxel (100 mg/m2, 3 wks on/1 off) x ≥6 Primary Endpoints: PFS, OS Stratification: Liver metastases; prior taxane; PD-L1 status www.clinicaltrials.gov, September 2016. Identifier: NCT02425891 Emens LA et al. Proc ASCO 2016;Abstract TPS1104.

“In patients with AR-positive disease who are not eligible for clinical trials, it is reasonable to obtain enzalutamide or bicalutamide on compassionate use if the patient does not need an immediate response.” Hope S Rugo, MD

Ongoing Phase III Trials of PARP Inhibitors in TNBC or BRCA Mutation-Positive Breast Cancer Trial name N Eligibility Randomization OlympiAD 310 gBRCA+ mBC Olaparib Placebo OlympiA 1,500 High-risk HER2- primary BC gBRCA+ Brightness 624 Early-stage TNBC Veliparib + carboplatin + paclitaxel  AC Placebo + carboplatin + paclitaxel  AC Placebo + placebo + paclitaxel  AC EMBRACA 429 Unresectable metastatic or locally advanced HER2- BC ≤3 chemotherapy regimens for mBC Talazoparib Physician’s choice www.clinicaltrials.gov, September 2016.

Utility of 21-Gene Recurrence Score and 70-Gene Signature “We do tend to use the 21-gene score a lot about decisions about chemotherapy for node-negative disease. And then we tend to use the 70-gene score a little bit more about decisions in terms of trial participation in the neoadjuvant setting and in differentiating difficult situations where patients have a lot of bulk of disease.” Hope S Rugo, MD

SWISH: Prevention of Everolimus-Associated Stomatitis Treatment included: Everolimus 10 mg and exemestane 25 mg QD 10 mL of commercially available 0.5 mg/mL dexamethasone oral solution, swish x 2 min and spit QID for 8 weeks Stomatitis Grade % Study All 1 2 3 4 SWISH at 8 weeks (N = 92) 19.8 17.4 2.4 BOLERO-2 (total) 67 34 25 8 Rugo HS et al. Proc ASCO 2016;Abstract 525.

Steroid Mouthwashes and Everolimus-Associated Stomatitis “I believe that this should now be our standard of care for patients receiving the mTOR inhibitor everolimus, because we can tremendously improve the rate of stomatitis and, therefore, quality of life.” Hope S Rugo, MD

Potential Management Approaches for mTOR Inhibitor-Associated Fatigue and Pneumonitis Methylphenidate Dose reductions/treatment holiday Rule out other etiology — hypothyroidism, polypharmacy Interstitial pneumonitis If only radiographic evidence, no further intervention If Grade 2, stop drug and administer steroids as needed Resume drug once patient is recovered

Practical Considerations for Use of Cooling Cap Systems Facility/Personnel Availability of freezer space (does not apply to DigniCap) Personnel time/postcooling time

Practical Considerations for Use of Cooling Cap Systems Facility/Personnel Availability of freezer space (does not apply to DigniCap) Personnel time/postcooling time Patient Cost Discomfort Time Restrictions on shampooing/styling of hair

Phase II/III Trial of OPT-822/OPT-821 Vaccine Therapy in Patients with mBC OPT-822: Globo-H/keyhole limpet hemocycanin (KLH) conjugate Globo H is glycolipid highly expressed in BC OPT-821: Adjuvant for vaccine N = 349 patients randomized 2:1 to subcutaneous OPT-822/OPT-821 or control until PD (with low-dose cyclophosphamide) No difference was observed in PFS (p = 0.77) or in interim OS (p = 0.29) PFS and OS were significantly improved in the 50% of patients who developed a Globo H-specific IgG response to OPT-822/OPT-821 any time during treatment OPT-822/OPT-821 was well tolerated with the most common drug-related adverse event being Grade 1/2 injection reaction. Huang C-S et al. Proc ASCO 2016;Abstract 1003.

Palbociclib + fulvestrant Efficacy of Palbociclib and Fulvestrant in Patients with mBC and ESR1 Mutations N = 395 patients with successful ESR1 mutation analysis from PALOMA-3 trial ESR1 mutations were strongly associated with acquired resistance to prior aromatase inhibitors Median PFS (months) Palbociclib + fulvestrant Placebo + fulvestrant HR (p-value) ESR1-positive (n = 67; 39) 9.4 4.1 0.524 (0.0052) ESR1-negative (n = 198; 91) 9.5 3.8 0.438 (<0.0001) Palbociclib offers high efficacy regardless of ESR1 mutation status Turner NC et al. Proc ASCO 2016;Abstract 512.

Clinical Data with CDK4/6 Inhibitors Ribociclib and Abemaciclib in ER-Positive mBC MONALEESA-2: A Phase III trial of first-line ribociclib + letrozole versus letrozole alone Clinically significant improvement in PFS with ribociclib + letrozole MONARCH1: A Phase II trial of abemaciclib after endocrine therapy and chemotherapy In N = 132 patients, ORR = 19.7% Phase II trial of abemaciclib in patients with brain metastases secondary to HR-positive mBC, NSCLC or melanoma Exploratory analysis of n = 3 patients with mBC treated with abemaciclib detected abemaciclib and its active metabolites in resected brain metastases Press release, May 18, 2016. Novartis; Dickler MN et al. Proc ASCO 2016;Abstract 510; Sahebjam S et al Proc ASCO 2016;Abstract 526.

ExteNet: DFS at 2-Year Follow-Up (Intent to Treat) Neratinib (n = 1,420) Placebo (n = 1,420) Hazard ratio p-value DFS including DCIS 93.9% 91.0% 0.63 0.0017 Invasive DFS (IDFS) 91.6% 0.67 0.0091 HR-positive 95.4% 91.2% 0.51 0.0013 HR-negative 92.0% 92.2% 0.93 0.74 Neratinib for 12 months post-trastuzumab significantly improved 2-yr IDFS Grade 3/4 diarrhea was the most common adverse event leading to dose reductions/discontinuation of neratinib in 26%/17% of patients Chan A et al. Lancet Oncol 2016;17(3):367-77.

KEYNOTE-012: Possible Immune-Mediated Adverse Events One case each: Grade 3 colitis Grade 3 hepatitis Grade 2 hypothyroidism Case of colitis reported 40 days after last pembrolizumab dose and after patient started subsequent therapy with capecitabine One case of Grade 2 enterocolitis accompanied by Grade 3 diarrhea reported 136 days after last pembrolizumab dose and 94 days after the start of eribulin. Nanda R et al. J Clin Oncol 2016;34(21):2460-7.

CREATE-X: A Phase III Trial of Adjuvant Capecitabine in HER2-Negative BC with Pathologic Residual Invasive Disease After Neoadjuvant Chemotherapy Capecitabine Control HR (p-value) 2-year DFS rate 87.3% 80.5% 0.688 (0.001) 2-year OS rate 96.2% 93.9% 0.658 (0.086) Lee S-J et al. San Antonio Breast Cancer Symposium 2015;Abstract S107.

MA.17R: A Phase III Trial of Extended Adjuvant Letrozole Placebo HR (p-value) 5-year DFS rate 95% 91% 0.66 (0.01) 5-year OS rate 93% 94% 0.97 (0.83) Annual incidence rate —contralateral BC 0.21% 0.49% 0.42 (0.007) Bone-related toxic events occurred more frequently with letrozole Bone pain Bone fractures New-onset osteoporosis Goss PE et al. N Engl J Med 2016:375(3):209-19.

PALOMA-2: A Phase III Trial of First-Line Palbociclib with Letrozole Palbociclib + letrozole (n = 444) Placebo + letrozole (n = 222) HR (p-value) Median PFS 24.8 mo 14.5 mo 0.58 (<0.000001) Hematologic AEs, % Palbociclib + letrozole (n = 444) Placebo + letrozole (n = 222) Any grade Grade 3 Grade 4 Neutropenia 80 56 10 6 1 <1 Leukopenia 39 24 2 Anemia 5 9 Thrombocytopenia 16 Finn RS et al. Proc ASCO 2016;Abstract 507.

MONARCH-1: A Phase II Study of Single-Agent Abemaciclib in HR+/HER2-Negative mBC After Chemotherapy In N = 132 heavily pretreated patients, abemaciclib demonstrated single-agent activity: ORR = 19.7% Median PFS = 6.0 mo Median OS = 17.7 mo Select most common AEs All grade Grade 3 Grade 4 Creatinine increased 98.5% 0.8% Diarrhea 90.2% 19.7% Neutrophil decreased 87.7% 22.3% 4.6% Platelet count decreased 41.4% 2.3% Dickler MN et al. Proc ASCO 2016;Abstract 510.

Abemaciclib + anastrozole neoMONARCH: A Phase II Neoadjuvant Trial of Abemaciclib or Anastrozole Alone or the Combination Trial Identifier: NCT02441946 Enrollment: 148 (Closed) Abemaciclib Eligibility Postmenopausal HR+/HER2-negative breast adenocarcinoma Clinical Stage I (≥1 cm), Stage II, Stage IIIA or IIIB R After day 14 all pts receive the combination for 14 weeks Anastrozole Abemaciclib + anastrozole Primary endpoint: Change in Ki-67 levels between baseline and after 2 weeks of therapy www.clinicaltrials.gov, September 2016.

monarcHER: A Phase II Randomized Trial of Abemaciclib in Locally Advanced or Metastatic BC Trial Identifier: NCT02675231 Enrollment: 225 (Open) Eligibility Postmenopausal HR+/HER2-positive breast adenocarcinoma Must have received: Taxane T-DM1 At least 2 anti-HER2 agents for advanced disease Abemaciclib + trastuzumab + fulvestrant R Abemaciclib + trastuzumab Trastuzumab + standard chemotherapy Primary endpoint: Progression-free survival www.clinicaltrials.gov, September 2016.

ASCO Practice Guideline: Use of Biomarkers to Guide Adjuvant Systemic Therapy Decisions For a patient with ER/PR-positive/HER2-negative, node-positive breast cancer, the clinician should not use certain biomarkers to guide adjuvant treatment decisions, including those below: Oncotype DX EndoPredict MammaPrint PAM50 Breast Cancer Index Mammostrat Immunohistochemistry 4 Harris LN et al. J Clin Oncol 2016;34(10):2460-7.

6 cycles of neoadjuvant therapy KRISTINE: A Phase III Trial of Neoadjuvant HER2 Targeted Therapy with or without Chemotherapy Docetaxel S U R G E Y Carboplatin Trastuzumab TCH+P Centrally confirmed HER2- positive, operable, locally advanced or inflammatory breast cancer Tumor >2cm Trastuzumab Pertuzumab Pertuzumab R 6 cycles of neoadjuvant therapy 12 cycles of adjuvant HER2-therapy T-DM1 T-DM1 T-DM1+P Pertuzumab Pertuzumab pCR in breast and lymph nodes: THCP = 56%, T-DM1 + P = 44% Hurvitz SA et al. Proc ASCO 2016;Abstract 500.

BCIRG-006: 10-Year Follow-Up DFS (≥4 positive nodes): TCH = 62.9%, AC-TH = 62.8%, AC-T = 53.6% Therapeutic Index: AC  TH TCH DFS events (n = 1,074; 1,075) 269 279 Grade 3/4 CHF (n = 1,068; 1,056) 21 4 Totals 290 283 Rx-related leukemias (n = 1,068; 1,056) 7(8)* 0(1)† Sustained LVEF loss >10% (n = 1,042; 1,031) 200 97 * Only in AC-Rx patients; † Leukemia developed after CHOP Rx Slamon DJ et al. Proc SABCS 2015;Abstract S5-04.