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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
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