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Jointly provided by & This activity is supported by educations grants from Novartis Pharmaceuticals Corporation, Pfizer, and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com Use of Novel Combination Therapies in Treatment of Advanced HR+/HER2- Breast Cancer A CME-certified ONCOLOGY EXCHANGE Activity

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STAGING: AJCC TNM Classification for Breast Cancer AJCC Cancer Staging Manual, 8 th Edition. Breast Cancer. The American College of Surgeons. 2018

AJCC Cancer Staging Manual, 8 th Edition. Breast Cancer. The American College of Surgeons. 2018 STAGING: AJCC TNM Classification for Breast Cancer

Changing Landscape of ER-positive Metastatic Breast Cancer Tamoxifen approved1970-80 Anastrozole approved1996 Fulvestrant approved 2002 Fulvestrant HD approved 2012 Everolimus approved 2012 Palbociclib approved 2015 Ribociclib / Abemaciclib approved 2017 Combination therapies

Educational ObjectivesEvaluate the updated clinical guidelines for combination therapies in the treatment of HR+/HER2- advanced breast cancer patients Integrate clinical data regarding the use of CDK 4/6 inhibitors and mTOR inhibitors to treat HR+/HER2- advanced breast cancer, including appropriate patient subpopulationsMitigate toxicities associated with multi-drug treatment regimens to improve patient outcomes Recognize potential drug-drug interactions to plan effective and safe treatment regimens for each patient

AgendaWelcome, Introduction, and Pre-survey Current Guidelines for Combination Therapy with Endocrine AgentsAlleviation of Side Effects Associated with Best Practice Combination Therapies Novel Agents and Emerging Clinical Data for HR+ Breast CancerQ&A Session and Concluding Remarks

Polling Question 1 Pre-activity Survey70-year-old female presents with hip pain. Past history is significant for stage 2 breast cancer diagnosed 20 years ago, at which time she received 5-years of tamoxifen. Imaging demonstrates multiple areas consistent with probable bone metastases. Bone biopsy shows adenocarcinoma consistent with breast primary, ER-positive 95%, PR-negative, HER2-negative. She receives anastrozole and has stable disease for 24-months, at which point she develops progressive disease in her bones. All of these are reasonable second-line therapeutic options EXCEPT: TamoxifenLetrozoleFulvestrant plus palbociclib or abemaciclib Exemestane plus everolimusFulvestrant

Polling Question 2 Pre-activity Survey65-year-old post-menopausal female presents with a palpable right breast mass. Imaging confirms a mass in the right breast, as well as several enlarged lymph nodes. Breast biopsy demonstrates invasive ductal cancer, grade 1, ER-positive, PR-positive, HER2-negative. Systemic staging demonstrates enlarged nodes in the mediastinum, as well as bone metastases. She undergoes a bone biopsy that confirms metastatic breast cancer, ER-positive, PR-positive, HER2-negative. All of these are reasonable first-line therapeutic options EXCEPT: FulvestrantFulvestrant plus anastrozoleLetrozole plus a CDK inhibitor Exemestane plus everolimus

Current Guidelines for Combination Therapy with Endocrine Therapy

SWOG S0226 Phase III Trial of Anastrozole + Fulvestrant 250 vs Anastrozole Alone Mehta RS et al N Engl J Med. 2012;367:435-444. FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO qday * ANASTROZOLE 1 mg PO qday * n = 707 Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease Primary PFS Secondary OS FUL + ANA n = 355 ANA n = 352 HR P value PFS ( mo ) 15.0 13.5 0.80 0.007 OS ( mo ) median 47.7 41.3 0.81 0.049 *Crossover to fulvestrant 500 mg allowed after progression

FACT: Phase III Study of Anastrozole + Fulvestrant 250 vs Anastrozole Alone Bergh J et al. J Clin Oncol. 2012;30:1919-1925. FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO qday ANASTROZOLE 1 mg PO qday n = 514 Pre/Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease Primary TTP Secondary TTF, ORR, CBR, Safety, OS FUL + ANA n = 256 ANA n = 254 HR P value TTP (mo) 10.8 10.2 0.72 0.91 OS (mo) median 37.8 38.2 1.00

Palbociclib PD 0332991 CDK 4/6 Inhibitors Approved by the FDA Ribociclib LEE011 Abemaciclib LY2835219

PALOMA 1: Progression-Free Survival Finn R et al. Presented at: American Association for Cancer Research 2014 Congress; April 5-9, 2014; San Diego, CA. Abstract CT101. Time (Month) PAL+LET 84 67 60 47 36 28 21 13 8 5 1 LET 81 48 36 28 19 14 6 3 3 1 Number of patients at risk PAL + LET (n=84) LET (n=81) Number of Events (%) 41 (49) 59 (73) Median PFS, months (95% CI) 20.2 (13.8, 27.5) 10.2 (5.7, 12.6) Hazard Ratio (95% CI) 0.488 (0.319, 0.748) P -value 0.0004

PALOMA 1: Final Overall Survival PAL+LET (n=84) LET(n=81) Patients with events, n (%) 60 (71) 56 (69) Median OS, months (95% CI) 37.5 (31.4, 47.8) 34.5 (27.4, 42.6) Hazard ratio (95% CI) 0.897 (0.623, 1.294) P -v alue 0.281 Finn R et al. Presented at: American Society of Clinical Oncology 2017. PAL+LET 84 73 63 38 28 13 8 LET 81 67 52 33 21 10 3 Time (Month) Number of patients at risk

PALOMA-2 and MONALEESA-2 Design of Phase III Studies Primary endpoint: PFS Secondary endpoints: Response, OS, safety, biomarkers, PROs PALOMA-2 RANDOMI SE Palbociclib (125 mg qd, 3/1 schedule) + letrozole (2.5 mg qd) Placebo + letrozole (2.5 mg qd) Postmenopausal ER+ HER2– advanced breast cancer with no prior treatment for advanced disease. AI-resistant patients excluded n = 666 (2:1) Stratified by the presence/absence of liver and/or lung metastases Ribociclib (600 mg qd, 3 wk on/1 wk off schedule) + letrozole (2.5 mg qd) Placebo + letrozole (2.5 mg qd) Primary endpoint: PFS Secondary endpoints: OS (key), ORR, CBR, safety Postmenopausal women with HR+/HER2– advanced breast cancer with no prior therapy for advanced disease n = 668 MONALEESA-2 RANDOMI SE (1:1) PRO = patient-reported outcome; qd = once daily

PALOMA-2 Finn RS et al. N Engl J Med . 2016;375:1925-1936. MONALEESA-2 PALOMA-2 & MONALEESA-2: PFS mPFS (months) Ribociclib –letrozole: 25.3 Placebo–letrozole: 16.0 Hazard ratio, 0.568 (95% CI, 0.457-0.704 ) mPFS (months) Palbociclib–letrozole: 24.8 Placebo–letrozole: 14.5 Hazard ratio, 0.58 (95% CI, 0.46-0.72) Hortobagyi GN et al. J Clin Oncol . 2017;35(suppl):Abstract 1038.

MONARCH 3: Study Design

Di Leo et al. Presented at: European Society for Medical Oncology (ESMO) 2017. Primary Endpoint (PFS) Met at Interim Analysis

MONALEESA-7 Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter Primary analysis planned after ~329 PFS eventsStratified by:Presence/absence of liver/lung metastases Prior chemotherapy for advanced diseaseEndocrine therapy partner (tamoxifen vs NSAI) Primary endpoint PFS (locally assessed per RECIST v1.1)‡ Secondary endpointsOverall survival (key) Overall response rate Clinical benefit rate Safety Patient-reported outcomes Pre/ perimenopausal women with HR+, HER2– ABC No prior endocrine therapy for advanced disease ≤1 line of chemotherapy for advanced disease n =672 Randomization (1:1) Ribociclib (600 mg/day; 3-weeks-on/ 1-week-off) + tamoxifen/NSAI + goserelin * n=335 Placebo + tamoxifen/NSAI + goserelin * n=337 Phase III Placebo-controlled Study of Ribociclib and Tamoxifen /NSAI + Goserelin NSAI = non-steroidal aromatase inhibitor; RECIST = Response Evaluation Criteria in Solid Tumors. *Tamoxifen = 20 mg/day; NSAI: anastrozole = 1 mg/ day or letrozole = 2.5 mg/day; goserelin = 3.6 mg every 28 days; ‡ PFS by Blinded Independent Review Committee conducted to support the primary endpoint. 1. Klijn JG et al. J Clin Oncol. 2001;19:343-353. 2. Mourisden H et al. J Clin Oncol. 2001;19:2596-2606.

Primary Endpoint: PFS Investigator-assessed Probability of progression-free survival (%) PFS (investigator assessment) Ribociclib + tamoxifen / NSAI ( n=335) Placebo + tamoxifen / NSAI ( n=337) Number of events, n (%) 131 (39.1) 187 (55.5) Median PFS, months (95% CI) 23.8 (19.2–NR) 13.0 (11.0–16.4) Hazard ratio (95% CI) 0.553 (0.441–0.694) One-sided P-value 0.0000000983 10 8 6 4 2 0 100 80 60 40 20 0 30 28 26 24 22 20 18 16 14 12 10 30 50 70 90 Tripathy D et al. Presented at: 2017 SABCS . Abstract GS2-05.

PFS by Endocrine Therapy Partner Investigator-assessedGoserelin included in all combinations. PFS (investigator assessment) Tamoxifen NSAI Ribociclib arm n=87 Placebo arm n=90 Ribociclib arm n=248 Placebo arm n=247 Number of events, n 39 55 92 132 Median PFS, months (95% CI) 22.1 (16.6–24.7) 11.0 (9.1–16.4) 27.5 (19.1–NR) 13.8 (12.6–17.4) Hazard ratio (95% CI) 0.585 (0.387–0.884) 0.569 (0.436–0.743)

Patient-reported Outcomes EORTC QLQ-C30 – Global Health Status QoL = quality of life. Goserelin included in all combinations. Ribociclib + tamoxifen /NSAI ( n=335) Placebo + tamoxifen /NSAI ( n=337) Number of events, n (%) 102 (30.4) 115 (34.1) Median, months (95% CI) NR (22.2–NR) 21.2 (15.4–23.0) Hazard ratio (95% CI) 0.699 (0.533–0.916) Log -rank test P-value 0.004 Time to deterioration (months) 80 90 60 50 70 40 30 20 10 0 100 10 8 6 4 2 0 28 26 24 22 20 18 16 14 12 Event-free probability (%)

EFECT Endocrine Therapy in Hormone-refractory MBC Proportion of patients progression-free Months At risk: Fulvestrant Exemestane 3.7 3.7 Median (months) HR = 0.963, 95% CI (0.819, 1.133), p=0.6531 Cox analysis, p=0.7021 Exemestane Fulvestrant Fulvestrant* Exemestane 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 351 195 96 50 25 12 4 2 342 190 98 41 21 12 8 6 0 1 0 0 Chia S et al. J Clin Oncol. 2008;26:1664-1670. *500mg D1 250mg D14, q28d

PALOMA3 Study Design Presented by Turner N at: 2015 ASCO Annual Meeting.

Primary Endpoint: PFS (ITT Population) Presented by Turner N at: 2015 ASCO Annual Meeting. Turner NC et al. N Engl J Med. 2015;373:209-219.

* Dose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg BID after 178 patients enrolled Sledge GW Jr et al. J Clin Oncol. 2017;35:2875-2884.MONARCH 2: Study Design HR+/HER2- ABC Pre/peri-  or postmenopausal ET resistant: Relapsed on neoadjuvant or on/within 1 yr of adjuvant ET Progressed on first-line ET No chemo for MBC No more than 1 ET for MBC ECOG PS ≤1 abemaciclib: 150 mg  * BID (continuous schedule) fulvestrant: 500 mg  Primary endpoint: Investigator-assessed PFS Secondary endpoint: OS, Response, Clinical Benefit Rate, Safety Stratification factors: - Metastatic site - ET resistance (primary vs secondary) placebo: BID (continuous schedule) fulvestrant: 500 mg  Randomization 2 :1 n  = 669

Primary Endpoint: PFS (ITT) Median PFS abemaciclib + fulvestrant: 16.4 months placebo + fulvestrant: 9.3 months HR (95% CI): 0.553 (0.449, 0.681) P <0.0000001 PFS benefit confirmed by blinded independent central review (HR: 0.460; 95% CI: 0.363, 0.584; P <0 .000001)

Change from baseline (%) 100 0 -100 -50 -30 50 20 Previously-treated HR+/HER2− MBC Abemaciclib 200 mg twice daily Treatment continued until unacceptable toxicity or PD Dickler et al. J Clin Oncol . 2016; 34 : abstr act 510. MONARCH 1 Investigator Assessed Response a Abemaciclib 200  mg BID (n   =   132) Confirmed overall response rate (ORR; complete response + partial response) (95   % CI) 19.7% (13.3-27.5) Complete response Partial response 0% 19.7% Stable disease (SD) ≥ 6 mo 22.7% Clinical Benefit Rate (ORR + SD ≥ 6 mo ) 42.4 %

Acquired Resistance to Endocrine Therapy in ER+ BC ER Gene expression E E Estrogen (E) Estrogen receptor (ER) Aromatase A Androgen (A) Some ways acquired resistance may occur: Activation of growth factor signaling pathways (PI3K/ AKT/ mTOR ; MAPK/ ERK; etc.) ER mutations Changes in the tumor microenvironment Acquired resistance is defined as: PI3K AKT mTOR Ras MAPK RTK Receptor tyrosine kinases (RTK) Recurrence at least 12 months after completion of adjuvant therapy Disease progression ≥6 months after endocrine therapy initiated in the metastatic setting Bachelot T et al. J Clin Oncol . 2012;30:2718-2724; Bedard PL et al. Breast Cancer Res Treat . 2008;108:307-317.

Primary Resistance to Endocrine Therapy in ER+BC ER Gene expression E E Estrogen (E) Estrogen receptor (ER) Aromatase A Androgen (A) Primary resistance is defined as Recurrence within adjuvant therapy Disease progression < 6 months after treatment in the metastatic setting Some ways primary resistance may occur: FGFR amplifications Loss of ER α Post-translational modification of ER α Expression of ER cofactors MYC amplification and overexpression Cyclin D1 amplification or expression PI3K AKT mTOR MAPK RTK Receptor tyrosine kinases (RTK) Ras Bachelot T, et al. J Clin Oncol . 2012;30(22):2718-2724; Bedard PL, et al. Breast Cancer Res Treat . 2008;108(3):307-317

Everolimus in Hormone-refractory MBC TAM 4.5 mo. TAM + RAD 8.6 mo. Hazard Ratio (HR) = 0.53 (95% CI: 0.35-0.81) Exploratory log-rank: P =0.0026 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of survival 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months Time (weeks) HR = 0.36 (95% CI: 0.27–0.47) EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months Log rank P value = 3.3 x 10 -15 0 12 6 18 24 30 36 48 60 42 54 72 66 78 80 60 40 20 100 0 Probability of Event (%) Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) Baselga J et al . N Engl J Med . 2012;366:520-529. Bachelot T et al . J Clin Oncol . 2012;30:2718-2724.

Fulvestrant ± Everolimus : PFSPresented at: San Antonio Breast Cancer Symposium, December 6-10, 2016

MANTA Study Design Fulvestrant + Vistusertib(intermittent schedule; 2d on 5d off) Fulvestrant + Everolimus ER+, HER2- ABC Postmenopausal Measurable or evaluable disease Disease refractory to AI Relapsed on or ≤12 months from adjuvant AI, or Progressed on AI in the advanced setting Max. 1 line of chemotherapy Fulvestrant + Vistusertib (Continuous daily schedule) Fulvestrant R n=90 n=90 n=60 n=60 Primary endpoint: Investigator-assessed PFS Secondary endpoints: Response rates (ORR) Clinical benefit rate (CBR) Duration of response OS Safety Fulvestrant : 500 mg i.m . injection on day 1, 15 & 29, and then q28 days Everolimus : 10 mg o rally, once daily, continuous schedule Vistusertib (continuous): 5 0 mg o rally, twice daily, continuous schedule Vistusertib (intermittent): 125 mg o rally, twice daily, day 1&2 every week Stratification factors: Measurable Disease (vs non-measurable) Sensitivity to prior ER (sensitive vs resistant) Sensitivity to prior ET is defined as: ≥24 months of adjuvant ET before recurrence or CR or PR or SD for ≥24 weeks with ≥1 ET for MBC ET = endocrine therapy; ER = Estrogen Receptor, ABC = advanced breast cancer, AI = Aromatase inhibitor; PR/CR = Partial/Complete response, SD = stable disease, d = days; PFS = Progression-free survival Trial Sponsor: Queen Mary University of London.

25 50 75 100 Progression-free Survival (%) 0 30 Time (months) 12 24 18 6 Number at risk F+E 64 45 26 8 2 0 F 66 29 14 6 1 0 F +V cont F+V int 101 95 54 48 17 21 6 8 3 4 0 0 CI = confidence i nterval; ITT = i ntent-to-treat ; mths = months; PFS = progression-free survival F = Fulvestrant; F+E = Everolimus; F+V(cont) = Vistusertib, continuous schedule; F+V( int ) = Vistusertib, intermittent schedule (2 days on, 5 days off); San Antonio Breast Cancer Symposium, December 5-9, 2017 Primary Endpoint: PFS (ITT Population) Median PFS, months (95% CI) Fulvestrant + Vistusertib cont 7.6 (5.9-9.4) Fulvestrant + Vistusertib int 8.0 (5.6-9.9) Fulvestrant 5.4 (3.5-9.2) Fulvestrant + Everolimus 12.3 (7.7-15.7)

Alleviation of Side Effects Associated with Best Practice Combination Therapies

Polling Question 3 Activity Survey65-year-old postmenopausal woman from question above was treated with exemestane and everolimus. Twelve weeks into therapy, she complained of generalized rash and mild dyspnea on exertion. CXR showed apical changes consistent with pneumonia or pneumonitis. Treatment options would include all EXCEPT:CT chest Continue current medicationsOral antibiotics or steroidsPulmonary consult

Polling Question 4 Activity SurveyThe patient received CDK4/6 inhibitor and letrozole. Three weeks into treatment she develops fever, diarrhea, and an episode of syncope. At presentation in ER, her vitals were: temp 101 0F, pulse was 60/min, BP 90/60. Possible causes related to CDK4/6 inhibitor causing her symptoms include: Neutropenic feverHeart blockDiarrheaAll of the above

Ribociclib + Letrozole n = 334 Placebo + Letrozole n = 330 n (%) Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Total 331 (99.1) 232 (69.5) 56 (16.8) 322 (97.6) 117 (35.5) 6 (1.8) Neutropenia 214 (64.1) 139 (41.6) 29 (8.7) 16 (4.8) 3 (0.9) 0 Nausea 178 (53.3) 8 (2.4) 0 101 (30.6) 2 (0.6) 0 Fatigue 138 (41.3) 9 (2.7) 1 (0.3) 107 (32.4) 3 (0.9) 0 Diarrhea 128 (38.3) 8 (2.4) 0 81 (24.5) 3 (0.9) 0 Alopecia 115 (34.4) 0 0 53 (16.1) 0 0 Vomiting 112 (33.5) 12 (3.6) 0 55 (16.7) 3 (0.9) 0 Arthralgia 111 (33.2) 2 (0.6) 1 (0.3) 108 (32.7) 4 (1.2) 0 Constipation 93 (27.8) 4 (1.2) 0 71 (21.5) 0 0 Headache 90 (26.9) 1 (0.3) 0 69 (20.9) 2 (0.6) 0 Hot flush 82 (24.6) 1 (0.3) 0 84 (25.5) 0 0 Back pain 81 (24.3) 10 (3.0) 0 67 (20.3) 1 (0.3) 0 Cough 77 (23.1) 0 0 70 (21.2) 0 0 Neutrophil count decreased 72 (21.6) 53 (15.9) 3 (0.9) 4 (1.2) 1 (0.3) 0 Anemia 69 (20.7) 6 (1.8) 2 (0.6) 19 (5.8) 4 (1.2) 0 Decreased appetite 69 (20.7) 5 (1.5) 0 52 (15.8) 1 (0.3) 0 Palbociclib + Letrozole n = 444 Placebo + Letrozole n =222 n (%) Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Total 439 (98.9) 276 (62.2) 60 (13.5) 212 (95.5) 49 (22.1) 5 (2.3) Neutropenia 353 (79.5) 249 (56.1) 46 (10.4) 14 (6.3) 2 (0.9) 1 (0.5) Leukopenia 173 (39.0) 107 (24.1) 3 (0.7) 5 (2.3) 0 0 Fatigue 166 (37.4) 8 (1.8) 0 61 (27.5) 1 (0.5) 0 Nausea 156 (35.1) 1 (0.2) 0 58 (26.1) 4 (1.8) 0 Arthralgia 148 (33.3) 3 (0.7) 0 75 (33.8) 1 (0.5) 0 Alopecia 146 (32.9) 0 0 35 (15.8) 0 0 Diarrhea 116 (26.1) 6 (1.4) 0 43 (19.4) 3 (1.4) 0 Cough 111 (25.0) 0 0 42 (18.9) 0 0 Anemia 107 (24.1) 23 (5.2) 1 (0.2) 20 (9.0) 4 (1.8) 0 Back pain 96 (21.6) 6 (1.4) 0 48 (21.6) 0 0 Headache 95 (21.4) 1 (0.2) 0 58 (26.1) 4 (1.8) 0 Hot flush 93 (20.9) 0 0 68 (30.6) 0 0 Constipation 86 (19.4) 2 (0.5) 0 34 (15.3) 1 (0.5) 0 Rash 79 (17.8) 4 (0.9) 0 26 (11.7) 1 (0.5) 0 Asthenia 75 (16.9) 10 (2.3) 0 26 (11.7) 0 0 Finn RS et al. N Engl J Med . 2016;375:1925-1936. Hortobagyi GN et al. J Clin Oncol . 2017;35(suppl): Abstract 1038. PALOMA-2 MONALEESA-2 PALOMA-2 and MONALEESA-2: Toxicity

   20 % in either arm, n (%) AllG3 G4 AllG3 G4 Any 435 (98.6) 241 (54.6) 26 (5.9) 199 (89.2) 46 (20.6) 5 (2.2) Diarrhea  a 381 (86.4) 59 (13.4) 0 55 (24.7) 1 (0.4) 0 Neutropenia  b 203 (46.0) 104 (23.6) 13 (2.9) 9 (4.0) 3 (1.3) 1 (0.4) Nausea 199 (45.1) 12 (2.7) - 51 (22.9) 2 (0.9) - Fatigue 176 (39.9) 12 (2.7) - 60 (26.9) 1 (0.4) - Abdominal pain 156 (35.4) 11 (2.5) - 35 (15.7) 2 (0.9) - Anemia 128 (29.0) 31 (7.0) 1 (0.2) 8 (3.6) 2 (0.9) 0 Leukopenia 125 (28.3) 38 (8.6) 1 (0.2) 4 (1.8) 0 0 Decreased appetite 117 (26.5) 5 (1.1) 0 27 (12.1) 1 (0.4) 0 Vomiting 114 (25.9) 4 (0.9) 023 (10.3)4 (1.8)0 Headache89 (20.2)3 (0.7)-34 (15.2)1 (0.4)-Placebo + Fulvestrantn = 223 Abemaciclib + Fulvestrant n = 441 a  Grade 2 diarrhea: abemaciclib + fulvestrant n = 140 (31.7 %); placebo + fulvestrant n = 11 (4.9 %). b  Febrile neutropenia was uncommon [6 patients in the abemaciclib arm (1 incorrectly coded; 1 post-chemotherapy)] and was not associated with severe infection This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. TEAE (Safety Population)

SWISH Study Phase II single-arm trial evaluated prophylaxis with steroid mouthwash on everolimus-associated stomatitisMouthwash: 10ml with dexamethasone 0.5mg/5mL (swish for 2-mins and spit) QID for 8 to 16 weeks started day 1 of exemestane and everolimus92 patients enrolled with 85 evaluable Rugo HS et al. Lancet Oncol. 2017;18:654-662.

SWISH: Effect of Steroid Mouthwash on Everolimus -associated Stomatitis Rugo HS et al. Lancet Oncol. 2017;18:654-662.

Rare Everolimus -related Pulmonary Side Effects Grade SymptomsManagement Everolimus Dose Modification 1 Asymptomatic (radiographic findings only) Initiate appropriate monitoring No dose adjustment required 2 Symptomatic, not interfering with ADLs Rule out infection Consider treatment with corticosteroids Consider interruption of therapy until symptoms improve to grade ≤1 3 Symptomatic, interfering with ADLs; oxygen required Rule out infection Consider treatment with corticosteroids Reinitiate everolimus at a lower dose Discontinue treatment if failure to recover within 4 weeks Hold treatment until recovery to grade ≤1 4 Life threatening; ventilatory support indicated 12 (2.7) Consider reinitiating everolimus at a lower dose. If toxicity recurs at grade 3, consider discontinuation Discontinue everolimus Based on Everolimus Package Insert.

Novel Agents and Emerging Clinical Data for HR+ Breast Cancer

Where Do We Stand Today? First-Line Post-Progression CDKi + LET LET EXE TAM EVE + TAM EVE + EXE CDKi + FULV FULV PFS, months LET +/- CDK4/6i FULV +/- CDK4/6i EXE +/- EVE TAM +/- EVE

BELLE 2: Addition of Buparlisib (Pan-PI3K Inhibitor) to Fulvestrant in Hormone-resistant MBCCI = confidence interval; HR - hazard ratio; OS = overall survival; PFS = progression-free survival. Full Population (N=1047)Buparlisib + Fulvestrantn=576 Placebo + Fulvestrant n=571Median PFS, months (95% CI)6.9(6.8–7.8) 5.0 (4.0–5.2) HR (95% CI) 0.78 (0.67–0.89) One-sided P value <0.001 Probability of Progression-free Survival, % Time (Months) 100 60 0 80 40 20 0 4 8 14 18 2 6 10 12 16 20 26 30 22 24 28 Buparlisib + fulvestrant (n/N=349/576) Placebo + fulvestrant (n/N=435/571) Toxicity significant (80% grade ≥3 toxicities) PIK3CA mutations not predictive (in tissue) Baselga J et al. Presented at: San Antonio Breast Cancer Symposium (SABCS) 2015.

PFS results by independent central review were consistent with local assessment: HR 0.57 (95% CI: 0.44–0.74; one-sided P<0.001) BELLE 3 Progression-free Survival per Investigator Assessment CI = confidence interval; HR = hazard ratio. 6-month PFS rate: 31% vs. 20% 100 80 60 40 20 0 0 4 8 2 6 10 12 14 16 18 20 22 24 26 Time, Months Probability of Progression-free Survival, % Full Population (n=432) Buparlisib + Fulvestrant n=289 Placebo + Fulvestrant n=143 Median PFS, months (95% CI) 3.9 (2.8–4.2) 1.8 (1.5–2.8) HR (95% CI) 0.67 (0.53–0.84) One-sided P -value <0.001 Di Leo A et al. Lancet Oncol. 2018;19:87-100.

ER+/HER2- locally advanced or metastatic BC Postmenopausal Recurrence or progression during or after aromatase inhibitor SANDPIPER Phase 3 Study of Taselisib in ER+ MBC Primary Endpoint: PFS in pts with mutant tumors Target HR: 0.59 (mPFS 4.5  7.6 mo ) >95% power at two-sided 1% alpha level Stratify: 1) Visceral disease 2) Endocrine sensitivity 3) Geographic region 120 Pts without PIK3CA Mutant Tumors Taselisib 4 mg QD + Fulvestrant Placebo QD + Fulvestrant Taselisib 4 mg QD + Fulvestrant Placebo QD + Fulvestrant 2:1 randomization 2:1 randomization Treat until PD or unacceptable toxicity No Crossover Survival Data 480 Pts with PIK3CA Mutant Tumors Available at: www.ClinicalTrials.gov; NCT02340221.

Ongoing Trials α -specific PI3K inhibitors www.clinicaltrials.gov NCT02077933 Phase I alpelisib + everolimus +/- exemestane NCT 02437318 (SOLAR-1) Phase III fulvestrant +/- alpelisib NCT02340221 (Sandpiper) Phase III Fulvestrant +/- Taselisib NCT01923168 (Neo-Orb) Phase II Letrozole +/- Alpelisib or Buparlisib NCT 02273973 (Lorelei) Phase II Letrozole +/- Taselisib

Ribociclib (LEE011) Palbociclib (PD-0332991) Abemaciclib (LY2835219) PI3K AKT mTOR CCND1 CDK4/6 pRb E2F Cell survival Proliferation Other signals (AMPK/ERK/p90RSK) PI3K Inhibitor CDK4/6 Inhibition + α -PI3K Inhibition Combinations Could Reverse Resistance to Endocrine Therapy as well as CDK4/6 Therapy

1. Bardia et al. Presented at: SABCS 2015. Exemestane + Everolimus + Ribociclib Phase Ib /II Study of Postmenopausal Women with AI-resistant ER+ MBC 1 Letrozole + Alpelisib + Ribociclib Phase Ib Study of Postmenopausal Women with ER+ MBC 2 2. Juric et al. Presented at: SABCS 2015.

FGFR1 amplification is an independent predictor of overall survival in patients with ER+ breast cancer treated with tamoxifen FGFR1 amplification is present in ~15% of ER+ breast cancers Elbauomy Elsheikh S et al. Breast Cancer Res. 2007:9:R23. Karlsson E et al. Genes Chromosomes Cancer. 2011;50:775-787. Turner N et al. Cancer Res. 2010;70:2085-2094. Targeting FGFR Pre-surgical letrozole study shows FGFR1 amplification as a mechanism of endocrine resistance Combination of ER and FGFR inhibitors is synergistic against ER+/ FGFR1 -amp PDXs Formisano and Arteaga

* FGFR alteration = FGFR1-4 amplification Phase Ib/II trial of FGFR TKI erdafitinib + fulvestrant + CDK4/6 inhibitor in endocrine-resistant ER+/HER2– metastatic breast cancer with FGF pathway alterations (Mayer, I) Targeting FGFR Completed Safety and Efficacy of TK1258 in FGFR1 Amplified and Non-amplified Metastatic HER2 Negative Breast Cancer Condition: Metastatic Breast Cancer Intervention: Drug: TK1258 Completed A Phase II Trial Testing Oral Administration of Lucitanib in Patients with Fibroblast Growth Factor Receptor (FGFR)1-amplified or Non-amplified Estrogen Receptor Positive Metastatic Breast Cancer Condition: Breast Cancer Intervention: Drug: lucitanib Completed Has Results Safety and Efficacy of AZD4547 in Combination with Fulvestrant vs. Fulvestrant Alone in ER+ Breast Cancer Patients Condition: FGFR Inhibition, Pharmaconetics , Biomarkers; ER+ Breast Cancer Intervention: Drug: AZD4547; Drug: Exemestane; Drug: Placebo; Drug: Fulvestrant Active not recruiting AZD4547 & Anastrozole or Letrozole (NSAIs) in ER + Breast Cancer Patients Who Have Progressed on NSAIs (RADICAL) Condition: Breast Cancer Intervention: Drug: AZD4547/ anastrozole or letrozole Recruiting Open-Label, Dose-Escalation Study of INCB054828 in Subjects with Advanced Malignancies Condition: Malignant Solid Tumor; Carcinoma; Non-Small-Cell-Lung; Stomach Neoplasms; Urothelial Carcinoma; Endometrial Neoplasms; Multiple Myeloma; MPN; Breast Cancer: Cholangiocarcinoma Intervention: Drug: INCB054828; Drug: Gemcitabine+Cisplatin ; Drug: Pembrolizumab; Drug: Docetaxel Recruiting NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma Condition: Advanced Malignant Solid Neoplasm; Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Plasma Cell Myeloma; Refractory Malignant Neoplasm; Refractory Plasma Cell Myeloma

PD-1/L1 Immunotherapy in Breast Cancer Immune checkpoint inhibitors are effective in a variety of solid tumors In the metastatic setting: 20% ORR in TNBC 1,2 6–12% ORR in ER+ BC 3,4 In ER+ mBC resistant to endocrine therapy, total mutational burden increases 5 , but these tumors are still generally immunologically ‘cold’ Immunotherapy combination strategies that increase immune recognition through enhanced antigen presentation and/or increased T cell homing may increase immunotherapy response 1 Emens et al. Presented at: American Association for Cancer Research (AACR) 2015. 2 Nanda et al. Presented at: AACR 2015. 3 Dirix et al. JAVELIN trial. Presented at: SABCS 2015. 4 Rugo et al KEYNOTE-028 trial. Prsented at: SABCS 2015. 5 Lefebvre et al. PLoS Medicine. 2016;13:e1002201.

Immunotherapy Combination Strategies in ER+ MBC – CDK4/6 Inhibition Inhibition of CDK4/6 in ER+ breast cancer → Induction of senescence and enhanced recruitment of immune cells This may result in increased sensitivity checkpoint inhibitors TCGA CD8+ T cell marker expression correlates with expression of CXCL9 and CCL5 chemokines and high CXCL9 and CCL5 expression correlates with enhanced survival based on TCGA analysis of 1105 invasive breast cancers.

ENCORE 301 Exemestane ± Entinostat in HR-positive MBC with Prior Treatment with NSAI: Overall Survival Intent-to-treat population Yardley et al. Presented at: ASCO Breast 2011. www.ClinicalTrials.gov. NCT02115282.

Eligible: Advanced breast cancer ER/PR+, HER2- Progression/no progression on prior non-steroidal AI Exemestane plus Entinostat Exemestane plus Placebo Blood sampling: baseline, 2 wks Treatment until progression/intolerance: exemestane 25 mg daily po AND entinostat /placebo 5 mg po weekly. Proposed Schema RANDOMIZE n ≈ 600 ECOG 2112 A Randomized Phase III Trial of Endocrine Therapy plus Entinostat /Placebo in HR-Positive Metastatic Breast Cancer

Mutational Landscape of ER+ MBC Significant Genes with SNV and Indel Alterations Method: “MutSig” – Lawrence et al. 2014. This presentation is the intellectual property of Ofir Cohen. Contact them at (ofirc@broadinstitute.org) for permission to reprint and/or distribute. SNV = single nucleotide variant n=141

Acquired HER2 Mutations in ER+ MBC Presented at: SABCS – December 6-10, 2016. Kinase Domain Acquired (not observed in primary tumor) Shared (also observed in primary tumor) Unknown (primary tumor status unknown) ERBB2 ERBB2 mutations in 7% 83% of ERBB2 mutations (5/6) in metastatic samples with matched primaries were acquired. V777L L869R L755S G727A R143G S653C R1153L P1074L

ESR1 Mutation Background Presented by Turner N at 2016 ASCO Annual Meeting.

ESR1 Mutation Analysis by Digital PCR in the Randomized Phase III SoFEA Study Johnston SR et al. Lancet Oncol . 2013;989-998. O’Leary et al. Presented at: AACR, 2016. Fribbens C et al. J Clin Oncol . 2016;34:2961-2968 . Presented by Turner N at 2016 ASCO Annual Meeting. ESR1 Mutation Analysis by Digital PCR In the Randomized Phase III SoFEA Study

ESR1 Mutations in PALOMA-3 Presented b y Turner N at the 2016 ASCO Annual Meeting. ESR1 Mutations in PALOMA-3

PFS by ESR1 Mutation Status PFS = progression-free survival. March 2015 final PFS data cut; Cristofanilli et al. Lancet Oncol. 2016;17:425-439. Presented by Turner N at the 2016 ASCO Annual Meeting. PFS by ESR1 Mutation Status

Patient Information Brochures from CDC and Cancer.NetA copy has been provided with your syllabus Excellent tool to provide patientsCan be shipped to your office (minimal charge for postage)Available online with additional resources at:https://www.cdc.gov/cancer/breast/https://www.cancer.net/cancer-types/breast-cancer

Conclusions These are exciting times, as more and more (effective) therapies become available for the most common type of breast cancerBut, are targeted therapies a must at all times? If so, how are we going to sequence (or combine) all the approved and to-be-approved targeted therapies? At what cost (side effects and financial!)?Who knows?? Need to individualize based on patient and tumor characteristics…Whatever strategy ends up making a difference in overall survival is the one likely to prevail. Anything else, becomes physician/patient preference…

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