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Continuing the conversation in advanced breast cancer

touchCONGRESS Webinar

Funded by an independent medical education request from Eli Lilly

Highlights from ESMO 2018 – recorded October 2018

Dr. Javier Cortés Head of Breast Cancer ProgramIOB, Institute of Oncology, QuironSalud GroupMadrid & Barcelona, Spain

Disclosures

Applicability Company

(1) Advisory role yesRoche, Celgene, Cellestia, AstraZeneca,

Biothera Pharmaceuticals, Merus, Seattle Genetics

(2) Stock ownership/profit yes MedSIR

(3) Patent royalties/licensing fees n/a

(4) Lecture fees yes Roche, Novartis, Celgene, Eisai, Pfizer

(5) Manuscript fees n/a

(6) Scholarship/research fund yes Roche

(7) Other remuneration n/a

Webinar overview

ESMO, European Society for Medical Oncology; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive.

Focus on the management of HR+/HER2- advanced breast cancer▪ Where are we now?▪ ESMO 2018 – Efficacy (key clinical trial data)▪ ESMO 2018 – Securing optimal cancer care (key clinical trial data)

Focus on other therapies for advanced breast cancer▪ ESMO 2018 – Other breaking data

1

2

Please submit your questions throughout the presentation – these will be reviewed and answered at a later date.

Challenges in the management of HR+/HER2- advanced breast cancer

Part 1. Where are we now?

HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive.

Three selective CDK inhibitor therapies are approved

HR+/HER2- advanced breast cancer

Region Date Indication Approval study

Palbociclib

FDA Feb15 2L + letrozole PALOMA-2

EU Aug15 In combination with endocrine therapy

FDA Feb16 2L in combination with fulvestrant after endocrine therapy PALOMA-3

EU Nov16 2L in combination with aromatase inhibitor after endocrine therapy

EU Nov16 After endocrine therapy progression

FDA Mar17 1L in combination with aromatase inhibitor

Ribociclib

FDA Mar17 1L in combination with aromatase inhibitor* MONALEESA-2

EU Aug17 1L in combination with aromatase inhibitor* MONALEESA-2

Abemaciclib

FDA Sep17 2L in combination with fulvestrant after endocrine therapy MONARCH-2

FDA Sep17 Monotherapy in ABC after disease progression with endocrine therapy and chemotherapy MONARCH-1

FDA Feb18 1L in combination with aromatase inhibitor MONARCH-3

EU Oct18 1L or 2L in combination with an aromatase inhibitor or fulvestrant In pre- or peri-menopausal women, with endocrine therapy in combination with LHRH agonist

MONARCH-2MONARCH-3

*EU approval for locally advanced and metastatic; FDA approval for ABC.ABC, advanced breast cancer; 1L, first-line; 2L, second-line; CDK, cyclin-dependent kinase; CHMP, Committee for Medicinal Products for Human Use; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; LHRH, luteinising hormone-releasing hormone.

What challenges remain for optimizing treatment sequencing in advanced breast cancer?

CDK, cyclin-dependent kinase.1. Hart CD, et al. Nat Rev Clin Oncol 2015;12:541–52; 2. McCutcheon S, Cardoso F. Breast 2015;24:623-9; 3. Debald M, et al. EPMA J 2014;5(Suppl 1):A41.

• Heterogeneity of disease and new mutations1

• Development of treatment resistance1

• Patient conditions

DISEASE

• Sequence of treatment – inclusion of biologic agents1

• No defined biomarkers to identify patients who may benefit from addition of a CDK inhibitor

• Lack or heterogeneity of multidisciplinary treatment or specialized advanced breast cancer nurses2

TREATMENT

CLINICAL & ECONOMIC

• Lack of clear and applicable management guidelines or high-level evidence for treatment options2

• Increasing, negative impact on healthcare budgets3

Focus on CDK4/6 inhibitors for HR+/HER2- advanced breast cancer

Part 2. ESMO 2018 – Efficacy

ESMO, European Society for Medical Oncology; CDK, cyclin-dependent kinase; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive.

First-line Phase III CDK4/6 inhibitor studies: PFS

Median PFS 24.8 months (95% CI: 22-N:e.)

Median PFS 14.5 months (95% CI: 12.9-17.1)

PALOMA-21

MONALEESA-23

HR: 0.543 (95% CI: 0.409-0.723) p=0.000021

MONARCH-32

HR: 0.58 (95% Cl: 0.46-0.72) Two-sided p<0.001

HR: 0.568 (95% CI: 0.457-0.704) p<0.00009

Median PFSRibociclib + letrozole25.3 months (95% CI: 23.0-30.3)

Median PFSPlacebo + letrozole16.0 months (95% CI: 13.4-18.2)

Median PFSAbemaciclib + NSAI: not reachedPlacebo + NSAI: 14.7 months

Figure reproduced from Finn et al., 2016

Figure reproduced from Goetz et al., 2017

Figure reproduced from Hortobagyi et al., 2018

IMPORTANT: First-line PFS outcomes data are not directly comparable between the different Phase III studies

95% CI, 95% confidence interval; CDK, cyclin-dependent kinase; HR, hazard ratio; N:e., not evaluable; NSAI, non-steroidal aromatase inhibitor; ORR, objective response rate; PFS, progression-free survival. 1. Finn RS, et al. N Engl J Med 2016;375(20):1925–36; 2. Goetz MP, et al. J Clin Oncol 2017;35(32):3638–46; 3. Hortobagyi GN, et al. Ann Oncol 2018 Apr 27. doi: 10.1093/annonc/mdy155. [Epub ahead of print]; 4. Goetz M, et al. Abstract CT040: Presented at AACR 2018.

Final MONARCH-3 PFS data were presented at AACR 20184

Median PFS for abemaciclib + NSAI vs. placebo + NSAI • 28.2 vs. 14.8 months, respectively• HR, 0.54; 95% CI: 0.418–0.698; p=0.000002

PFS benefit from first-line endocrine-based therapies in postmenopausal women with HR+/HER2- MBC according to different prognostic subgroups: a combined analysis of data from PALOMA-2, MONALEESA-2, MONARCH-3, FALCON, SWOG and FACT TrialsRossi V, et al.

What’s new with CDK4/6 inhibitors at ESMO?

*MONALEESA-7 data were included in the poster analysis. 95% CI, 95% confidence interval; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; ECOG, Eastern Cooperative Oncology Group; ESMO, European Society for Medical Oncology; HR, hazard ratio; MBC, metastatic breast cancer; PFS, progression-free survival.Rossi V, et al. Poster 340P. Presented at ESMO 2018.

Identify which factors may guide the clinical choice of first-line endocrine-based therapies from a combined analysis of seven Phase III trials*

▪ Significant PFS benefit with all therapeutic options vs. AI endocrine-monotherapy (HR, 0.74; 95% CI: 0.67–0.80)

▪ Indirect comparison showed a significantly longer PFS in favour of the three classes of CDK4/6 inhibitors vs. endocrine-based therapies

▪ Similar results observed in subgroup analyses, including visceral vs. non-visceral metastases, Asian vs. non-Asian ethnicity, prior adjuvant chemotherapy, and prior endocrine therapy

▪ First-line treatment combinations of CDK4/6 inhibitors with AIs or fulvestrant showed significant 26% PFS risk reduction vs. AI monotherapy

▪ CDK4/6 inhibitors showed further PFS benefits in indirect comparisons with fulvestrant – no differences noted between individual CDK4/6 therapies

▪ Significant PFS benefits associated with CDK4/6 inhibitors also observed in patients with bone only and/or soft tissue-limited disease

OS with palbociclib plus fulvestrant in women with HR+/HER2− ABC: Analyses from PALOMA-3Cristofanilli M, et al.

What’s new with palbociclib at ESMO?

95% CI, 95% confidence interval; ABC, advanced breast cancer; ESMO, European Society for Medical Oncology; ESR1, oestrogen receptor 1; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; OS, overall survival; PFS, progression-free survival.Cristofanilli M, et al. LBA2_PR. Presented at ESMO 2018.

To determine the OS of palbociclib + fulvestrant in HR+/HER2- ABC with sensitivity to prior ET

▪ Median OS was numerically improved by 6.9 months in the palbociclib vs. placebo arm (median follow-up 44.8 months; stratified HR, 0.81; 95% CI: 0.644–1.029; 1-sided p=0.043)

▪ Palbociclib patients with sensitivity to prior ET showed a 10-month benefit in median OS vs. placebo + fulvestrant (HR, 0.72; 95% CI: 0.551–0.942; 1-sided p=0.008)

▪ In patients without sensitivity to prior ET, no OS benefit was observed in the palbociclib vs. placebo treatment arms

▪ Clinically meaningful PFS benefits of palbociclib + fulvestrant observed in PALOMA-3 (6.6 months vs. placebo + fulvestrant) were maintained for median OS, especially in patients with sensitivity to prior ET

▪ Non-significant improvements in median OS were observed with palbociclib + fulvestrant vs. placebo + fulvestrant, regardless of ESR1 mutation status or prior lines of therapy

Clinical outcomes in patients with ER+/HER2- ABC with OR or without OR in PALOMA-2Rugo HS, et al.

What’s new with palbociclib at ESMO?

95% CI, 95% confidence interval; ABC, advanced breast cancer; ESMO, European Society for Medical Oncology; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; MD, measurable disease; mDOR, median duration of objective response; mPFS, median progression-free survival; OR, objective response.Rugo HS, et al. Poster 332P. Presented at ESMO 2018.

Describe clinical outcomes of patients who achieved a confirmed OR in PALOMA-2 vs. patients without an OR

▪ OR was achieved in 43.7% (57.4% in patients with MD) and 34.7% (44.4% in patients with MD) of patients in the palbociclib + letrozole and placebo + letrozole arms, respectively

▪ mPFS was significantly prolonged with palbociclib + letrozole vs. placebo + letrozole in both OR (HR, 0.65; 95% CI: 0.46–0.92; p=0.007) and non-OR patients (HR, 0.55; 95%CI: 0.43–0.70; p<0.001)

▪ In palbociclib patients with MD with OR, 49.0% achieved OR within the first 3 months, 74.7% within 6 months, and 89.7% within 1 year

▪ In patients with OR, mDOR was longer with palbociclib + letrozole vs. placebo + letrozole (27.7 vs. 20.9 months, respectively)

▪ Palbociclib + letrozole provided significant clinical benefit vs. placebo + letrozole regardless of OR status

▪ Palbociclib + letrozole is an effective therapy option for patients with HR+/HER2- ABC

Ribociclib + fulvestrant for ABC: PFS subgroup and tumor response analyses from MONALEESA-3Jerusalem G, et al.

What’s new with ribociclib at ESMO?

2L, second-line; 95% CI, 95% confidence interval; ABC, advanced breast cancer; ESMO, European Society for Medical Oncology; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; MD, measurable disease; PFS, progression-free survival.Jerusalem G, et al. Poster 331P. Presented at ESMO 2018.

Additional efficacy and pain reduction results in patients receiving ≤1 line of prior endocrine therapy for ABC

▪ Median PFS with 2L ribociclib + fulvestrant was 18.8 months vs. 11.4 months with placebo + fulvestrant (HR, 0.539; 95% CI: 0.333–0.873)

▪ In patients with early relapse, median PFS was 13.1 months and 8.6 months for the ribociclib and placebo arms, respectively (HR, 0.591; 95% CI: 0.422–0.830)

▪ 41% of ribociclib patients with MD at baseline (95% CI: 35.9–45.8) and 29% (95% CI: 22.1–35.3) in the placebo arm had complete or partial response

▪ At Week 8, reductions in tumor size were reported in 68% of evaluable ribociclib patients vs. 55% in the placebo + fulvestrant group

▪ Ribociclib + fulvestrant demonstrated consistent PFS benefits in HR+/HER2- ABC patients in the 2L and early relapse settings

▪ Sustained tumor reductions were reported in a majority of these patients receiving ribociclib + fulvestrant, demonstrating consistency with studies of other ribociclib-based combinations

Abemaciclib with fulvestrant in patients with HR+/HER2- ABC that exhibited primary or secondary resistance to prior endocrine therapy Grischke E, et al.

What’s new with abemaciclib at ESMO?

95% CI, 95% confidence interval; ABC, advanced breast cancer; AE, adverse event; ESMO, European Society for Medical Oncology; HR, Hazard ratio; MD, measurable disease; ORR, objective response rate; PFS, progression-free survival.Grischke E, et al. Poster 329P. Presented at ESMO 2018.

Investigator-assessed PFS and safety of abemaciclib + fulvestrant in patients with primary or secondary resistance to prior endocrine therapy

▪ In patients with primary resistance, median PFS was 15.3 months vs. 7.9 months for abemaciclib + fulvestrant and placebo + fulvestrant, respectively (HR, 0.454; 95% CI: 0.306–0.674; p<0.0001)

▪ In patients with secondary resistance, median PFS also significantly favoured abemaciclib + fulvestrant vs. placebo + fulvestrant (16.6 vs. 9.6 months; HR, 0.591; 95% CI: 0.464–0.754; p<0.0001)

▪ ORR in MD was 53.9% and 46.2% for abemaciclib + fulvestrant in patients with primary and secondary resistance, respectively, vs. 17.9% and 22.6% for placebo + fulvestrant (p<0.001 vs. placebo)

▪ AEs were similar in patients with primary and secondary resistance to endocrine therapy

▪ In patients with primary or secondary resistance to endocrine therapy, abemaciclib + fulvestrant significantly improved PFS and ORR vs. placebo + fulvestrant

▪ Relatively larger PFS and ORR differences were reported in abemaciclib patients with primary endocrine resistance

Summary

• Investigation of first-line CDK4/6 inhibitor treatment combinations with AIs or

fulvestrant, show significant PFS benefits vs. AI monotherapy1

– Indirect comparisons suggest further PFS benefits vs. fulvestrant monotherapy1

• PALOMA-3 showed clinically meaningful benefits with palbociclib + fulvestrant,

especially in patients with sensitivity to prior ET2

• PALOMA-2 showed prolonged PFS rates with palbociclib + letrozole in patients

with or without an OR3

• In MONALEESA-2, ribociclib + fulvestrant demonstrated consistent PFS benefits in

second-line and early relapse settings4

– Sustained tumor reductions were reported with ribociclib therapy, demonstrating

consistency with other ribociclib-based combinations4

• In patients with primary or secondary ET resistance, abemaciclib + fulvestrant

significantly improved PFS and ORR vs. placebo + fulvestrant5

– Larger benefits were reported with primary endocrine resistance5

AI, aromatase inhibitor; CDK, cyclin-dependent kinase; ET, endocrine therapy; OR, objective response; ORR, objective response rate; PFS, progression-free survival.1. Rossi V, et al. Poster 340P. Presented at ESMO 2018; 2. Cristofanilli M, et al. LBA2_PR. Presented at ESMO 2018; 3. Rugo HS, et al. Poster 332P. Presented at ESMO 2018; 4. Jerusalem G, et al. Poster 331P. Presented at ESMO 2018; 5. Grischke E, et al. Poster 329P. Presented at ESMO 2018.

Figure reproduced from Harbeck & Gnant, 2017

Therapeutic strategies for advanced breast cancer

Previous treatments of patient’s preferences are key elements in deciding the individual therapeutic steps. Treatment decisions can thus differ for an individual patient. In patients with HR+/HER2- tumors, endocrine therapy should be the first option unless there is life-threatening disease. Chemotherapy is always an additional therapy option depending on the course of the disease. Al, aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PgR, progesterone receptor; TDM-1, trastuzumab emtansine. *If bone metastases: + bisphoshonates or denosumab. Always combine with ovarian suppression or ablation in premenopausal patients. Harbeck N, et al. Lancet 2017;389(10074):1134–50.

Symptoms or metastasis location*

Slow disease progression

Steroid hormone receptor status (ER, PgR)

ENDOCRINE THERAPY(± targeted therapy)

Al (e.g., letrozole) + CDK4/6i

Exemestane + everolimus or fulvestrant + CDK4/6i

ER or PgR positive, or both

Selected postmenopausal patients: Al + trastuzumab or

lapatinib (if HER2+)

Rapid therapy response required

HER2 status

CHEMOTHERAPY (± targeted therapy)

HER2+ + trastuzumab + pertuzumabTDM-1 single agent+ lapatinib/+ trastuzumabbeyond progression

HER2- ± bevacizumab (only first-line)

Depending on clinical situations

ER or PgR negative

Focus on CDK4/6 inhibitors for HR+/HER2- advanced breast cancer

Part 3. ESMO 2018 – Securing optimal cancer care

ESMO, European Society for Medical Oncology; CDK, cyclin-dependent kinase; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive.

Study Most common AEs Most common Grade 3/4 AEs Additional

PALOMA-21

PalbociclibNeutropenia (79.5%)Leukopenia (39.0%)Fatigue (37.4%)

Neutropenia (66.4%)Leukopenia (24.8%)Fatigue (1.8%)

Febrile neutropenia (1.8%)

PALOMA-32

PalbociclibNeutropenia (78.8%)Leukopenia (45.5%)Fatigue (38.0%)

Neutropenia (62.0%)Leukopenia (25.2%)Anaemia (2.6%)

Febrile neutropenia (0.6%)

MONALEESA-23

RibociclibNeutropenia (74.3%)Nausea (51.5%)Infections (50.3%)

Neutropenia (59.3%)Leukopenia (21.0%)Increase ALT (9.3%)

Increase in QTcF interval (2.7%)

MONARCH-24

AbemaciclibDiarrhoea (86.4%)Neutropenia (46.0%)Nausea (45.1%)Fatigue (39.9%)

Neutropenia (26.5%)Diarrhoea (13.4%)Leukopenia (8.8%)Anaemia (7.2%)

Thromboembolic events (2.0%)

MONARCH-35

AbemaciclibDiarrhoea (81.3%)Neutropenia (41.3%)Fatigue (40.1%)Nausea (38.5%)

Neutropenia (21.1%)Diarrhoea (9.5%)Leukopenia (7.6%)Anaemia (5.8%)

Thromboembolic events (4.9%)

Neutropenia and diarrhoea are the most common adverse events

Safety outcomes with CDK inhibitors

AE, adverse event; CDK, cyclin-dependent kinase.1. Finn RS, et al. N Engl J Med 2016;375:1925–1936; 2. Turner N, et al. N Engl J Med 2015;373(3):209–219; 3. Hortobagyi GN, et al. N Engl J Med 2016;375(18):1738–1748; 4. Sledge GW Jr, et al. J Clin Oncol 2017;35(25):2875–2884; 5. Goetz MP, et al. J Clin Oncol 2017;35(32):3638–3646.

Palbociclib Ribociclib Abemaciclib*

Haemogram q2w during the first 2-4 cycles → q4w

+ ++

Liver biochemistry q4w - ++

Creatinine q4w - -+

ECG q2w during the first 2 cycles - +-

Implications for tailored monitoring of patients treated with CDK inhibitors

Side-effect management in clinical practice

*Pro-active strategy to manage diarrhoea.CDK, cyclin-dependent kinase; ECG, electrocardiogram; q2w, every 2 weeks; q4w, every 4 weeks.Adapted from the clinical experience and practice of Dr. Javier Cortés, Head of Breast Cancer Program, IOB, Institute of Oncology, QuironSalud Group, Madrid & Barcelona, Spain.

Real world treatment patterns associated with palbociclib combination therapy in Germany: Results from the IRIS StudyMitra D, et al.

ESMO – Optimizing patient care (1)

1L, first-line; 2L, second-line; AI, aromatase inhibitor; ESMO, European Society for Medical OncologyMitra D, et al. Poster 338P. Presented at ESMO 2018.

Elucidate treatment patterns associated with palbociclib combination therapies in a German real-world clinical setting via a retrospective chart review

▪ Approximately 75% of patients received palbociclib + AI; 25% received palbociclib + fulvestrant

▪ 96.9% patients received palbociclib + AI as 1L advanced therapy, the rest had received prior chemotherapy

– 63.4% of patients received letrozole; 23.2% received anastrozole, 13.4% received exemestane

▪ Palbociclib + fulvestrant was mostly used in 1L (44.4%) and 2L (52.4%)

▪ Dose reduction rates were 10.8% with palbociclib + AI and 11.1% with palbociclib + fulvestrant

▪ Rates of palbociclib dose reduction were low in real-world practice and less frequent than observed in the PALOMA studies

▪ Similar dose reduction rates were reported for palbociclib with both AI and fulvestrant combinations

▪ The most frequent starting dose was 125 mg/day for both palbociclib combinations

First report of real-world patient characteristics and treatment patterns from POLARIS: Palbociclib in HR+ ABC – a prospective, multicentre, non-interventional studyBlum JL, et al.

ESMO – Optimizing patient care (2)

1L, first-line; ABC, advanced breast cancer; CDK, cyclin-dependent kinase; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; NSAI, non-steroidal aromatase inhibitor; ESMO, European Society for Medical Oncology.Blum JL, et al. Poster 344P. Presented at ESMO 2018.

Real-world, routine use of palbociclib for the treatment of patients with HR+/HER2- ABC

▪ Interim report of a prospective, non-interventional study of 1500 men and women from approximately 110 study sites

▪ Prior to starting palbociclib, 18.4% of patients received chemotherapy, 22.1% hormonal therapy, 5.5% radiotherapy, and 2.2% surgical resection

▪ Overall, 69.9% of patients received a 1L palbociclib combination therapy

– Of these, 56.6% received palbociclib + letrozole or anastrozole, 39.5% palbociclib + fulvestrant, and 3.9% palbociclib + exemestane

▪ First large, prospective, multicentre study to assess real-world use of a CDK4/6 inhibitor

▪ Palbociclib is usually combined with steroidal or NSAI agents, or fulvestrant, predominantly 1L

▪ In patients receiving 1L palbociclib combination therapy, the majority reported disease- and treatment-free intervals ≥36 months

PROs in ABC treated with ribociclib + fulvestrant: results from MONALEESA-3Fasching PA, et al.

ESMO – Optimizing patient care (3)

95% CI, 95% confidence interval; ABC, advanced breast cancer; AE, adverse event; ESMO, European Society for Medical Oncology; GHS, Global Health Status; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; HRQoL, health-related quality of life; PRO, patient-reported outcomes; QLS, quality of life scale; TTD, time to deteriorationFasching PA, et al. Poster 290O. Presented at ESMO 2018.

To evaluate HRQoL associated with ribociclib + fulvestrant in HR+/HER2- ABC

▪ Baseline global HRQoL scores were similar to those expected for metastatic ABC

▪ A numerical trend favoured ribociclib + fulvestrant vs. placebo + fulvestrant (TTD ≥10%; HR, 0.80; 95% CI: 0.60–1.05)

▪ Mean HRQoL (GHS/QLS scales) was maintained or improved during every cycle of treatment in both arms

▪ Similar impact across treatment arms for both fatigue (TTD ≥10%; HR, 0.96; 95% CI: 0.71–1.28) and pain scores (TTD ≥10%; HR, 1.00; 95% CI: 0.69–1.43)

▪ Global HRQoL was improved or maintained with treatment vs. baseline, but worsened at treatment cessation

▪ Delayed disease progression experienced with ribociclib was associated with maintained HRQoL

▪ AEs associated with ribociclib did not substantially impact HRQoL measures

Ribociclib + fulvestrant in HR+/HER2- ABC: MONALEESA-3 biomarker analysesNeven P, et al.

ESMO – Optimizing patient care (4)

ABC, advanced breast cancer; ESMO, European Society for Medical Oncology; ESR1, oestrogen receptor 1; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; mRNA, messenger ribonucleic acid; PFS, progression-free survival.Neven P, et al. Poster 346P. Presented at ESMO 2018.

Investigate the correlation between PFS and baseline biomarker (low vs. high expression)

▪ PFS hazard ratios favoured ribociclib + fulvestrant vs. placebo + fulvestrant across all biomarker subgroups

▪ PFS benefit associated with ribociclib + fulvestrant was consistent, regardless of Ki67 protein or CCND1 gene expression

▪ PFS benefit associated with ribociclib + fulvestrant was numerically greater in patients with low vs. high p16 protein expression, and low vs. high CDKN2A mRNA expression

▪ A similar trend was observed in patients with low vs. high ESR1 mRNA expression

▪ PFS was prolonged with ribociclib + fulvestrant vs. placebo + fulvestrant, irrespective of baseline biomarker expression

▪ Patients with low expression of p16 protein, CDKN2A or ESR1 mRNA levels demonstrate potentially greater PFS benefits with ribociclib therapy

Management of abemaciclib associated adverse events in patients with hormone receptor positive (HR+), HER2- advanced breast cancer: analysis of the MONARCH trialsRugo HS, et al.

ESMO – Optimizing patient care (5)

AE, adverse event; ESMO, European Society for Medical Oncology.Rugo HS, et al. Poster 339P. Presented at ESMO 2018.

To demonstrate that common AEs associated with abemaciclib may be managed effectively by dose reduction or omission

▪ Across the MONARCH studies, approximately 44% of patients experienced a diarrhea event (Grade ≥2); most cases were reported in the first treatment cycle

▪ In 17% of patients, primary management of diarrhea events comprised anti-diarrheal medication, dose omission, and dose reductions

▪ Neutropenia events (Grade ≥3) occurred in approximately 25% of patients across the MONARCH trials; maximal incidence was reported across the first 2 treatment cycles

▪ Supportive medication and/or a dose adjustment strategy was effective in managing AEs associated with abemaciclib across the MONARCH trials

▪ AE management strategies utilizing dose adjustments and/or supportive medication were effective

▪ Time on treatment can be extended by understanding and managing the safety profile of abemaciclib

Summary

1L, first-line; AI, aromatase inhibitor; HRQoL, health-related quality of life; NSAI, non-steroidal aromatase inhibitor; PFS, progression-free survival; PRO, patient-reported outcomes.1. Mitra D, et al. Poster 338P. Presented at ESMO 2018; 2. Blum JL, et al. Poster 344P. Presented at ESMO 2018; 3. Fasching PA, et al. Poster 290O. Presented at ESMO 2018; 4. Neven P, et al. Poster 346P. Presented at ESMO 2018; 5. Hugo HS, et al. Poster 339P. Presented at ESMO 2018.

• In the IRIS study, palbociclib dose reductions in real-world practice were low and

less than observed in the PALOMA studies1

– Dose reduction rates were similar with both AI and fulvestrant combinations1

• The POLARIS study suggested that patients predominantly receive palbociclib

therapy in the 1L setting, usually in combination with either an AI or NSAI,

or fulvestrant2

– In patients receiving 1L palbociclib combination therapy, the majority reported

disease- and treatment-free intervals ≥36 months2

• Analysis of PROs from MONALEESA-3 suggests delayed disease progression with

ribociclib is associated with maintained HRQoL3

• Biomarker findings from MONALEESA-3 suggest that patients with low expression

of p16 protein, CDKN2A or ESR1 mRNA levels may have greater PFS benefits

with ribociclib4

• Use of abemaciclib dose adjustments and/or supportive medication is an effective

management strategy for extending patient time on treatment5

Focus on other systemic therapies for advanced breast cancer

Part 4. ESMO 2018 – Other breaking data

ESMO, European Society for Medical Oncology

Alpelisib (ALP) + fulvestrant (FUL) for ABC: results of the Phase III SOLAR-1 trialAndré F, et al.

▪ PFS in the PIK3CA-mutant cohort was significantly longer with ALP + FUL vs. PBO + FUL (11.0 vs. 5.7 months, respectively) (HR, 0.65; 95% CI: 0.50–0.85; p=0.00065)

▪ ALP + FUL did not meet required proof of concept levels in the non-mutant cohort (7.4 vs. 5.6 months for ALP + FUL vs. PBO + FUL, respectively; HR, 0.85; 95% CI: 0.58–1.25)

▪ In patients with measurable PIK3CA-mutant ABC, ORR was 36% for ALP + FUL vs. 16% for PBO + FUL (p=0.0002)

▪ ALP + FUL is a potential new treatment option for patients with PIK3CA-mutant HR+/HER2- ABC who have progressed on prior ET with or without a CDK4/6 inhibitor

A focus on other systemic therapies (1)

95% CI, 95% confidence interval; ABC, advanced breast cancer; ALP, alpelisib; atezo, atezolizumab; CDK, cyclin-dependent kinase; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; FUL, fulvestrant; ITT, intention-to-treat; nab-P, nab-paclitaxel; mTNBC, locally advanced or metastatic triple-negative breast cancer; ORR, objective response rate; OS, overall survival; PBO, placebo; PD-L1, Programmed death-ligand 1; PFS, progression-free survival.André F, et al. LBA3_PR. Presented at ESMO 2018.; Schmid P, et al. LBA1_PR. Presented at ESMO 2018.

IMpassion130: Results from a global, randomized, double-blind, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs. placebo + nab-P in treatment-naïve mTNBCSchmid P, et al.

▪ Atezo + nab-P significantly improved PFS in both the ITT (HR, 0.80; 95% CI: 0.69–0.92; p=0.0025) and PD-L1+ populations (HR, 0.62; 95% CI: 0.49–0.78; p<0.0001), which was clinically meaningful for PD-L1+

▪ In the PD-L1+ population, atezo + nab-P was associated with a significant improvement in median OS of 25 months vs. 15.5 months with PBO + nab-P (OS HR, 0.62; 95% CI: 0.45–0.86; p=0.0035)

▪ Atezo + nab-P was well tolerated and should be considered a new standard of care for PD-L1+ tumours

A Phase III trial of chidamide, a subtype-selective HDAC inhibitor, in combination with exemestane in patients with HR+ ABCJiang Z, et al.

▪ Postmenopausal patients with HR+/HER2- ABC who failed on tamoxifen and/or NSAI▪ Median PFS was significantly improved with chidamide + exemestane vs. placebo + exemestane (median

PFS 7.4 vs. 3.8 months; HR, 0.755; 95% CI: 0.582–0.978; p=0.034)▪ ORR was 18.4% and 9.1% for chidamide + exemestane and placebo + exemestane, respectively (p=0.026);

CBR was 46.7% and 35.5%, respectively (p=0.034)▪ The most common Grade 3/4 AEs in the chidamide group were haematological: neutropenia (50.8% vs.

2.5% in the placebo group), thrombocytopenia (27.5% vs. 2.5%), and leukopenia (18.8% vs. 2.5%)▪ This was the first pivotal clinical study to demonstrate significant PFS benefits of an oral HDAC inhibitor

combined with exemestane

A focus on other systemic therapies (2)

95% CI, 95% confidence interval; ABC, advanced breast cancer; AE, adverse event; CBR, clinical benefit rate; HDAC, histone deacetylase; HER2-, human epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+, hormone receptor positive; NSAI, non-steroidal aromatase inhibitor; ORR, objective response rate; OS, overall survival; PBO, placebo; PFS, progression-free survival.Jiang Z, et al. 283O_PR. Presented at ESMO 2018.

Summary

ABC, advanced breast cancer; ET, endocrine therapy; HDAC, histone deacetylase; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; mTNBC, metastatic triple-negative breast cancer; NSAI, non-steroidal aromatase inhibitor; PD-L1, Programmed death-ligand 1; PFS, progression-free survival.1. André F, et al. LBA3_PR. Presented at ESMO 2018; 2. Schmid P, et al. LBA1_PR. Presented at ESMO 2018; 3. Jiang Z, et al. 283O_PR. Presented at ESMO 2018.

• In SOLAR-1, alpelisib + fulvestrant significantly improved PFS in patients with

PIK3CA-mutant vs. placebo + fulvestrant1

– Alpelisib + fulvestrant is a potential new treatment combination for patients with

PIK3CA-mutant HR+/HER2- ABC who have progressed on prior ET1

• Atezolizumab + nab-paclitaxel provided a meaningful PFS benefit in treatment-

naïve, PD-L1+ patients with locally advanced or mTNBC vs. placebo +

nab-paclitaxel2

– Atezolizumab + nab-paclitaxel may be considered as a new standard of care for

PD-L1+ tumors2

• In postmenopausal HR+/HER2- patients who failed tamoxifen and/or NSAI, the oral

HDAC inhibitor chidamide demonstrated significant PFS improvements vs. placebo,

combined with a backbone of exemestane3

– This was the first pivotal clinical study of an oral HDAC inhibitor combined with

exemestane3

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