Endocrine Therapy for Advanced Breast Cancer (ABC)Dr Yoon-Sim YAP Division of Medical Oncology,National Cancer Centre Singapore

2

DISCLOSURE SLIDE

Personal COI:Consultancy/Honoraria/Travel/Research Support• Astra Zeneca, Eisai, Lilly, Novartis, Pfizer, Roche

3

Outline

• Guidelines and Evolving Clinical Treatment Landscape for HR+ HER2- advanced breast cancer (ABC)

• Endocrine therapy backbone

• Targeted therapies to Overcome Endocrine Resistance– First Line setting – Second-line setting & beyond

• Conclusions

Treatment guidelines for HR+, HER2– advanced breast cancer

ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first choice independent of metastatic site, unless rapid response is needed. Limited visceral metastases are not a contraindication for endocrine therapy

ABC2 Endocrine therapy is the preferred option for HR+ disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response

ASCO3 Endocrine therapy should be recommended as initial treatment for patients with HR+ metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy.

NCCN4 Endocrine therapy recommended unless there is visceral crisis, or progression with no clinical benefit after 3 sequential endocrine therapy regimens.

4

1. Cardoso F et al. Ann Oncol 2012;23(Suppl 7):vii11-vii19 2. Cardoso F et al. Ann Oncol2014;25(10):1871–1888 3. ASCO 2016. Available at https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2016-adv-endocrine-breast-summary-table.pdf 4. NCCN V3.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

5

Breakthroughs in hormone receptor positive (HR+) breast cancer

1977Tamoxifen

1996Goserelin

1999Exemestane

2002Fulvestrant

2015Palbociclib

+ Letrozole

2016Palbociclib

+Fulvestrant

1997Letrozole

FDA approvals of new treatments

2012Everolimus

+ Exemestane

Com

bina

tion

The

rapy

19951980 2000 20162015

End

ocrin

e T

hera

py

2017Ribociclib(with AI)

2017

2017Abemaciclib(single agent

or with fulvestrant)

1995Anastrozole

1985MegestrolAcetate

2018

2018Abemaiclib

+NSAI

6

ASCO Guidelines

Rugo et al, JCO 2016

PostmenopausalPremenopausal

Probably due for update soon

7

4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)

Cardoso et al, Ann Onc 2018

Courtesy of Ian Smith from ESMO 2014

To consider oophorectomy, especiallyif going to need monthly (vs 3mthly) GnRH analogue for a long time (unless patient is too unstable for oophorectomy or decline).

Challenges of assessing menopausal status.Ovarian ablation with radiotherapy can be unpredictable and unreliable, so not often used now.

Mechanism of Action of Tamoxifen and Aromatase Inhibitors

Johnston, Nature Reviews Cancer 2003

First-line Comparative Tamoxifen Trials in Advanced Breast Cancer 1981 -96

11

Tamoxifen versus

N=17Progestogens 6

Estrogens 1

Androgens 1

Anti-Estrogens 2

Aminogluthetimide 3

Formestane 1

Fadrozole 2

Fulvestrant 1

Tamoxifen always better or at least as good.Schiavon and Smith, Haematol Oncol Clin North AM 2013

In 86 clinical studies, with total of 5353 patients,RR 30%; SD 20%; median response duration 15-24mths

Litherland et al, Ca Trt Rev 1998

Rationale for OS + Tamoxifen in Premenopausal MBC

Randomised study: n=161 (original target 348)Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by • objective response rate (48%, 34%, and 28% of patients

who could be evaluated, respectively; P = .11 [x2 test]), • median progression-free survival (9.7 months, 6.3

months, and 5.6 months; P = .03), and• overall survival (3.7 years, 2.5 years, and 2.9 years; P =

.01).• 5-year survival were 34.2% (95% confidence interval [CI]

= 20.4%–48.0%), 14.9% (95% CI =3.9%–25.9%), and 18.4% (95% CI = 7.0%–29.8%), respectively.

12

Klijn et al, JNCI 2000

Use of 2nd line AIs v megesterol acetate

AIs: RR, TTP and overall survival only slightly better than megestrol acetate

Smith NEJM 2003

Progestins

• Mechanism of action unclear. • May inhibit aromatase activity or increase

estrogen turnover, since estrogen levels fall during therapy.

• May also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor.

• Activity appears to be maintained in patients who are refractory to SAIs.

• Side-effects: weight gain, fluid retention, thromboembolic complications, PV bleeding.

Willemse, EJC 1990; Abrams, JCO 1999

What is the optimal 1 st-line endocrine therapy?

15

TrialAI

(response rate, %)

Tamoxifen (response

rate, %)AI (PFS, mths)

Tamoxifen(PFS, mths)

Hazard Ratio

Nabholtz et al, 2000 (n=353)Anastrozole vs tamoxifen 21 17 11.1 5.6 0.81

Bonneterre et al, 2001 (n=668)Anastrozole vs tamoxifen 33 33 8.2 8.3 0.99

Mouridsen et al, 2001 (n=907)Letrozole vs tamoxifen 30 20 9.4 6.0 0.72

Paridaens et al, 2008 (n=371)Exemestane vs tamoxifen 46 31 9.9 5.8 0.84

Range 8–12 6–8

PFS / TTP of AIs as 1 st-line endocrine therapy trials in HR+ MBC

No overall survival benefit with AI in individual trials.

Meta-analysis: compared to tamoxifen, there was a statistically significant survival benefit (11 percent relative hazard reduction, 95% CI 1 to 19 percent) for first-line third generation SAIs, but not for aminoglutethimide or second generation SAIs. (Mauri et al, JNCI 2006)

AI + Ovarian Suppression in Premenopausal

• Is it better than tamoxifen + ovarian suppression??

• No randomised trials with tamoxifen and OS for comparison in metastatic setting.

16

MONALEESA -7: Phase III placebo -controlled study of ribociclib and tamoxifen/NSAI + goserelin

• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

• Primary analysis planned after ~329 PFS events

– 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of 660 patients

• 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.

Stratified by:

• Presence/absence of liver/lung

metastases

• Prior chemotherapy for advanced disease

• Endocrine therapy partner (tamoxifen vs

NSAI)

Primary endpoint

• PFS (locally assessed per

RECIST v1.1)‡

Secondary endpoints

• Overall 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

Tripathy, SABCS 2017; Lancet Oncology 2018

Primary endpoint: PFS (investigator-assessed)

• CI, confidence interval; NR, not reached.Goserelin included in all combinations.

Pro

ba

bil

ity

of

PF

S (

%)

Time (months)No. at risk

Ribociclib + tamoxifen/NSAI 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0

Placebo + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0

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

1086420

100

80

60

40

20

0

30282624222018161412

10

30

50

70

90

Tripathy, SABCS 2017

PFS by endocrine therapy partner (investigator-assessed)

PFS (investigator assessment)

Tamoxifen NSAI

Ribociclib armn=87

Placebo armn=90

Ribociclib armn=248

Placebo armn=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)

• Goserelin included in all combinations.

Tripathy, SABCS 2017

NSAI + OS appears to be at least just as efficacious as, if not more efficacious than Tamoxifen + OS.

What are the endocrine options after AI?

• How good is tamoxifen after an AI?– TAMRAD (Tamoxifen vs Tamoxifen + Everolimus after AI) (Bachelot

et al, JCO 2012) Tamoxifen arm (26% received 1 line of palliative chemo): 6mth clinical benefit rate 42%; TTP 4.5 mths; response rate 13%

• How good is exemestane (monotx) after an AI?– EFECT (Chia, JCO 2008): median TTP 3.7mths; response rate

6.7%– SOFEA (Johnston, Lancet Oncol 2013): median PFS 3.4mths;

response rate 2.8%– BOLERO-2 (Baselga, NEJM 2012): median PFS 2.8mths, response

rate 0.4%.

• How good are progestins after an AI?– No prospective data

• How good is fulvestrant after an AI?– See following ….

20

Nodimerisation

NOTRANSCRIPTION(no tumour celldivision)

AF1 + AF2INACTIVE

Fulvestrant

AF1

ER+F F F

ACCELERATED RECEPTOR DEGRADATION

Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.

Mode of Action of Estradiol, Tamoxifen and Fulvestrant

Tamoxifen

AF1

ER+PARTIALLY INACTIVATEDTRANSCRIPTION(reduced rate oftumour celldivision)

T TT

AF1

AF1 ACTIVE

AF2INACTIVE

AF1

EREE

E+ AF1 + AF2

ACTIVEReceptor

dimerisation

FULLY ACTIVATEDTRANSCRIPTION(tumour celldivision)

AF2

AF1

Estradiol

22

Fulvestrant: Preclinical Activity

Osborne et al, JNCI 1995 Osborne et al, Cancer Chemo and Pharm 1994

23

Clinical Trials on Fulvestrant (250mg LD)

Howell, JCO 2004

Howell, JCO 2002 Osborne, JCO 2002

Only just as good as tamoxifen or anastrozole

Treatment-naive

Pretreated Pretreated

24

Clinical Trials on Fulvestrant (250mg LD)

Only just as good as exemestaneeven after relapse/progresson on non-steroidal AICaveat: 250mg dose was suboptimal

Johnston, Lancet Oncol 2013

Chia, JCO 2008

CONFIRM phase III Trial: Fulvestrant 250mg vs 500mg

Di Leo et al, JNCI 2014

Median OS 26.4mths vs 22.3mths

26

Clinical Trials on Fulvestrant (500mg HD)

Ellis et al, JCO 2015

Caveat: OS not preplanned analysis; not all patients participated in OS followup.

Primary Endpoint: CBR fulvestrant HD vs anastrozole72.5% v 67.0% (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P .386).

Robertson et al, JCO 2009

� ER +ve , HER2 negative� Locally advanced (not suitable for

surgery) or metastatic disease� Up to 1 line of chemotherapy� At least 1 lesion that can be assessed

FALCON: Phase III 1 st line study of Fulvestrant 500 vs AI in Endocrine Therapy Naïve MBC / LABC

• Primary endpoint: PFS• Secondary endpoint: OS

– Other secondary endpoints include ORR, CBR, duration of response, duration of clinical benefit, time to deterioration of HRQoL, Safety

Fulvestrant

500mg i.m.

Anastrozole

1mg OD

N=450

Note no prior endocrine therapy allowed

Ellis et al, LBA14 ESMO 2016

FALCON: Fulvestrant 500 vs anastrozole in 1st-line endocrine therapy naïve ER+ MBC

HR 0.797 (95% CI 0.637, 0.999) p=0.0486

Median PFSFulvestrant: 16.6 monthsAnastrozole: 13.8 months

Number of patients at risk:Fulvestrant

Anastrozole230232

187194

171162

150139

124120

110102

9684

8160

6345

4431

2422

1110

20

00

Pro

port

ion

of p

atie

nts

aliv

e an

d pr

ogre

ssio

n fr

ee

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 3 6 9 12 15 18 21 24 27 30 3633 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

PFS without visceral disease

HR 0.59 (95% CI 0.42, 0.84)

Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 monthsP

ropo

rtio

n of

pat

ient

s al

ive

and

prog

ress

ion-

free

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2

0 5 10 15 20 25 30 35 40

Fulvestrant (n=95) Anastrozole (n=113)

PFS with visceral disease

Pro

port

ion

of p

atie

nts

aliv

e an

d pr

ogre

ssio

n-fr

eeTime (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 5 10 15 20 25 30 35 40

0.2

HR 0.99 (95% CI 0.74, 1.33)

Median PFS Fulvestrant: 13.8 monthsAnastrozole: 15.9 months

Fulvestrant (n=135)

Anastrozole (n=119)

Primary endpoint: PFS

Ellis et al, LBA14 ESMO 2016; Robertson et al, Lancet 2016

What is the optimal 1 st-line endocrine therapy?

29

Trial Date AI (months)

Tamoxifen(months)

AI + fulvestrant 250mg (months)

Fulvestrant500mg

(months)Hazard Ratio

Nabholtz et alAnastrozole vs tamoxifen 2000 11.1 5.6 - 0.81

Bonneterre et al Anastrozole vs tamoxifen 2001 8.2 8.3 - 0.99

Mouridsen et al Letrozole vs tamoxifen 2001 9.4 6.0 - 0.72

Chernozemsky et alExemestane vs tamoxifen 2007 12.0 8.3 - -

Paridaens et alExemestane vs tamoxifen 2008 9.9 5.8 - 0.84

Mehta et alAnastrozole vs anastrozole + fulvestrant 250mg

2012 13.5 - 15.0 0.80

Bergh et alAnastrozole vs anastrozole + fulvestrant 250mg

2012 10.2 - 10.8 0.99

Ellis et alAnastrozole vs Fulvestrant500mg

2016 13.8 16.6 0.797

Range 8–13 6–8 10–15 16-17

PFS / TTP of AIs as 1 st-line endocrine therapy trials in HR+ MBC

Is Fulvestrant the gold standard for 1st-line treatment now?• PFS benefit “modest”• PFS benefit restricted to patients without visceral mets.• Only applies to endocrine naïve patients?• Activity of other endocrine therapies post-fulvestrant unclear.• Await overall survival data …. …….• Other more effective alternative options available now.

30

ESR1 Mutations

Toy et al, Nature Genetics 2013

New generation SERDs (Selective Estrogen Receptor Degraders - oral)

• Limitations of fulvestrant– Poor bioavailability– Requires oil-based IM formulation; limitations with

increasing dose intensity– Variable ER down-regulation

31

Van Kruchten et al, 2015

SERD Company Current statusGDC-0810 Genentech Phase I/II

GDC-0927 Genentech Phase I

RAD1901 Radius Phase I

AZD9496 Astra Zeneca Phase I

LSZ-102 Novartis Phase I

SAR439859 Sanofi Phase I

H3b-6545 (SERCA) H3 BioMedicine Phase I

FDA Breakthrough Drug Designation 2017

Definitions of Endocrine Resistance in ER+ MBC

PRIMARY ENDOCRINE RESISTANCE Relapse while on the first 2 years of

adjuvant ET, or PD within first 6 months of 1 st line ET for MBC, while on ET

PRIMARY ENDOCRINE RESISTANCE Relapse while on the first 2 years of

adjuvant ET, or PD within first 6 months of 1 st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE Relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET,

or PD ≥ 6 months after initiating ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE Relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET,

or PD ≥ 6 months after initiating ET for MBC, while on ET

Johnston, SABCS 2016; Cardoso, Annals Onc 2014 and Ann Onc 2018

What can we add to endocrine therapy to overcome endocrine resistance?

33

• First-line setting– CDK4/6 Inhibitor(Trials using Temsirolimus, Bevacizumab, EGFR Inhibitors negative or mixed results.)

• Second-line and beyond– CDK4/6 Inhibitor vs mTOR Inhibitor– ? PI3K inhibitor

Cyclin Dependent Kinase(CDK) 4/6 Inhibitors

34

Lange and Yee, Endocrine Related Cancer 2011Ma, ASCO 2016

CDK4/6 Inhibitors

O’Leary et al, Nat Rev Clin Onc 2016

PALOMA -2, MONALEESA -2, MONARCH-3: Design of Phase III Studies

• Primary endpoint: PFS• Secondary endpoints :

– Response, OS, safety, biomarkers, PROs

PALOMA-2

RANDOMISE

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)

Ribociclib (600 mg QD,

3/1 schedule) +letrozole

(2.5 mg QD)

Placebo+ letrozole

(2.5 mg QD)

Postmenopausal women with HR+/HER2–advanced breast cancer with

no prior therapy for advanced disease

N=668

MONALEESA-2

RANDOMISE

(1:1)

MONARCH-3

PALOMA -2, MONALEESA -2, MONARCH 3: PFS

28.18 m

25.3 m16.0 m0.568

; Ann Onc 2018; AACR 2018

PALOMA -2, MONALEESA -2, MONARCH 3: Toxicity

Goetz, ASCO 2018

MONARCH-1: Abemaciclib (Inhibitor of CDK4>CDK6)

39Dickler et al, ASCO 2016; CCR 2017

• Phase 2 single-agent trial in metastatic HR+HER2- mBC.• No. of prior systemic regimens (any setting); 5 (2-11).• 1-2 chemotherapy regimens in metastatic setting.

CDK 4/6 inhibitors for ER+ MBC

• New “Gold Standard” in 1st-line treatment • Adjuvant trials have also commenced.

Unanswered Questions

• Does every patient need CDK4/6 inhibitor upfront?

Potential Predictors of CDK4/6 Inhibitor Activity

In sensitive cell lines:

• ↑ Cyclin D1 (CCND1)

• ↑ Retinoblastoma (Rb)

• ↓ p16

Finn RS, et al. Br Ca Research 2009

ER+HER2- Unselected

ER+HER2- Plus Amplification of CCND1 and/or Loss of p16

PALOMA-1

Finn RS, et al. Lancet Oncol 2015

No specific biomarkers predictive of

differential CDK inhibitor benefit identified:

PALOMA-1, PALOMA-2, PALOMA-3

MONALEESA-2, MONALEESA-3

Subgroup Analyses

42

Hortobagyi

et al, NEJM

2016

Finn et al, NEJM 2016

PALOMA-2

MONALEESA-2

Goetz et al,

JCO 2017

MONARCH-3

Considerations in choosing 1 st-line therapy in ER+ MBC

Tumour Biology• ER & PR levels • Luminal Subtype / Proliferation

Clinical Features• Prior Endocrine Rx / DFI / Pace of Disease• Visceral vs non-visceral mets / Symptoms / Tumor Burden

Patient Factors• Age / Co-morbidities / Geographical Logistics • Patient Preference / Availability of Rx / Quality of Life

Partly adapted from Johnston, SABCS 2016

CDK 4/6 inhibitors for ER+ MBC

• New “Gold Standard” in 1st-line treatment• Adjuvant trials have also commenced.

Unanswered Questions• Does every patient need CDK4/6 inhibitor upfront?

• Will there be improvement in Overall Survival?

PALOMA -1 OS data (not powered)

45

Finn et al, ASCO 2017

Clinical Benefit Scale or Value Framework

• Use of objective scales, such as the ESMO Magnitude of Clinical Benefit Scale or the ASCO Value Framework, to evaluate the real magnitude of benefit provided by a new treatment and help prioritize funding, particularly in countries with limited resources.

• Eg Toxicity and QOL adjustment when only a PFS improvement.

46Schnipper et al, JCO 2016; Cherny et al, Ann Onc 2015

Improvement in QOL reported in

MONALEESA-7, PALOMA-3

No change in QOL with

PALOMA-2, MONALEESA-2,

MONALEESA-3, MONARCH2

CDK 4/6 inhibitors for ER+ MBC

• New “Gold Standard” in 1st-line treatment.• Adjuvant trials have also commenced.

Unanswered Questions• Does every patient need CDK4/6 inhibitor upfront?

• Will there be improvement in Overall Survival?

• What is the optimal treatment after CDK4/6 Inhibition?

• What is the optimal sequence of treatment?

Second -Line and Beyond

BOLERO-2 & PALOMA -3: Design of Phase III studies

Also MONARCH -2 and MONALEESA -3

(2:1)

Palbociclib (125 mg QD; 3 weeks on, 1

week off) + fulvestrant (500 mg

IM Q4W)(n=347)

Placebo (3 weeks on, 1 week

off) + fulvestrant (500 mg IM Q4W)

(n=174)

HR+, HER2- ABC

Pre/peri or postmenopausal

Progressed on prior ET on or within 12 months of adjuvant therapy and/or on therapy for advanced breast cancer

1 or more prior chemotherapy regimen for advanced cancer

• Primary endpoint: PFS• Secondary endpoints:

– OS, ORR, Safety, QoL, CBR

(2:1)

Everolimus 10 mg daily +

exemestane 25 mg daily(n=485)

Placebo + exemestane 25 mg daily

(n=239)

Postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole

• Primary endpoint: PFS• Secondary endpoints:

– OS, OR, CBR, Safety, QoL

BOLERO-2 PALOMA-3

RANDOMISE

RANDOMISE

BOLERO-2 & PALOMA -3: PFS

Turner N, et al. N Engl J Med 2015Baselga J, et al. N Engl J Med 2012

BOLERO-2PALOMA-3

MONARCH-2

Sledge et al. JCO 2017 Slamon et al. JCO 2017

MONALEESA-3

Consider use

of

fulvestrant +

everolimus if

there is

concern re

ESR1

mutation

BOLERO-2: Overall Survival Results

50

Piccart et al, Ann Onc 2014

Why?

Not statistically powered to detect 4.4mth OS benefit.

Imbalance in poststudy salvage chemo use?

Higher rate of discontinuation of EVE due to AE: 26% vs 5%

Paradoxical activation of AKT via negative feedback loop?

Need predictive biomarkers? Nil from genomic sequencing of tumor specimens

PALOMA 3 OS Update

51

Cristofanilli et al, ESMO 2018 and NEJM 2018

“Absolute improvement” in median OS was 6.9 monthsBUT ”not statistically significant.”The prespecified significance threshold was 1-sided 0.0235 which was adjusted for two interim OS analyses.

PI3K/AKT/mTOR Pathway

52

Rodon et al, Nature Reviews Clin Onc 2013

PI3K Inhibitors – still promising?

• Efficacy limited in unselected patients.• Significant toxicities with Pan-PI3K Inhibitors.

– FERGI (n=168): fulvestrant + pictilisib vs fulvestrant + placebo: negative

– BELLE2 (n=1147): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; benefit mainly with PIK3CA mutated (cDNA)

– BELLE3 (n=432)(post-mTOR inhibitor): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; benefit mainly with PIK3CA mutated (tumour or cDNA)

• Alpha-specific PI3K Inhibitors - Better tolerated?– Taselisib + fulvestrant vs placebo + fulvestrant (SANDPIPER)

(Baselga et al, ASCO 2018) met its primary endpoint (InvAx PFS in PIK3CA mutant (7.4m vs 5.4m; HR 0.70; p=0.0037) but toxicity issues!

– Alpelisib + fulvestrant vs placebo + fulvestrant (SOLAR) –following slide.

– Potential activity after progression on CDK4/6 Inhibitors?

53

SOLAR-1: Phase 3 RCT

54

Andre et al, ESMO 2018

SOLAR-1: Primary endpoint: Locally assessed PFS in the PIK3CA-mutant cohort

55

The primary endpoint crossed the prespecified Haybittle–Peto boundary (one-sided p≤0.0199).Toxicities: hyperglycaemia, rash.25.4% dose discontinuations due to Aes in experimental arm vs 4.7% in control arm.

Andre et al, ESMO 2018

Take Home Message(s)

• Endocrine therapy is the treatment of choice in advanced HR+HER2- breast cancer, unless patient is in visceral crisis or has exhausted endocrine therapy options.

• Addition of targeted treatments eg CDK inhibitor or everolimus (or alpelisib) can improve PFS; no evidence of OS benefit yet.

• Need to individualise choice of treatment based on tumour burden, tumour biology, and patient factors egcomorbidities, pt preference, access to treatments etc.

• Important to minimize toxicities and optimize QOL• Future directions: treatment beyond CDK inhibitors,

overcoming endocrine resistance, sequencing of treatments etc.

57

Thank you for your attention !

Pink Ribbon Walk, October 2016