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Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 1Activity Slides
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 STAGING: AJCC TNM Classification for Breast Cancer
AJCC Cancer Staging Manual, 8th Edition. Breast Cancer. The American College of Surgeons. 2018
AJCC Cancer Staging Manual, 8th Edition. Breast Cancer. The American College of Surgeons. 2018
STAGING: AJCC TNM Classification for Breast Cancer
Changing Landscape of ER-positive Metastatic Breast Cancer
Tamoxifenapproved
1970-80
Anastrozole approved
1996
Fulvestrantapproved
2002
Fulvestrant HD approved
2012
Everolimus approved
2012
Palbociclib approved
2015
Ribociclib/Abemaciclib
approved
2017
Combination therapies
Educational Objectives
• Evaluate 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 subpopulations
• Mitigate 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
Agenda
• Welcome, Introduction, and Pre-survey
• Current Guidelines for Combination Therapy with Endocrine Agents
• Alleviation of Side Effects Associated with Best Practice Combination Therapies
• Novel Agents and Emerging Clinical Data for HR+ Breast Cancer
• Q&A Session and Concluding Remarks
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 2Activity Slides
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
PrimaryPFS
SecondaryOS
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
PrimaryTTP
SecondaryTTF, 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
PalbociclibPD 0332991
CDK 4/6 Inhibitors Approved by the FDA
RibociclibLEE011
AbemaciclibLY2835219
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 SurvivalPAL+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-value 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
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 3Activity Slides
PALOMA-2 and MONALEESA-2 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)
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
RANDOMISE
(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: 25.3Placebo–letrozole: 16.0Hazard ratio, 0.568(95% CI, 0.457-0.704)
mPFS (months)Palbociclib–letrozole: 24.8Placebo–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 events
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/perimenopausalwomen 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: PFSInvestigator-assessed
Prob
abili
ty o
f pr
ogre
ssio
n-fr
ee s
urvi
val (
%)
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 D et al. Presented at: 2017 SABCS. Abstract GS2-05.
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 4Activity Slides
PFS by Endocrine Therapy PartnerInvestigator-assessed
Goserelin included in all combinations.
PFS (investigator assessment)
Tamoxifen NSAIRibociclib arm
n=87Placebo arm
n=90Ribociclib arm
n=248Placebo 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
1086420 282624222018161412
Even
t-fre
e pr
obab
ility
(%)
EFECTEndocrine Therapy in Hormone-refractory MBC
Prop
ortio
n o
f pat
ient
s pr
ogre
ssio
n-fre
e
MonthsAt risk:Fulvestrant
Exemestane
3.73.7Median (months)
HR = 0.963, 95% CI (0.819, 1.133), p=0.6531
Cox analysis, p=0.7021
ExemestaneFulvestrant
Fulvestrant*
Exemestane
0 3 6 9 12 15 18 21 24 270.0
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 neoadjuvantor 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
Ran
dom
izat
ion
2 :1n = 669
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 5Activity Slides
Primary Endpoint: PFS (ITT)
Median PFSabemaciclib + 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)
Cha
nge
from
bas
elin
e (%
)
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: abstract 510.
MONARCH 1Investigator Assessed Responsea Abemaciclib 200 mg BID
(n = 132)
Confirmed overall response rate (ORR; complete response + partial response) (95 % CI)
19.7% (13.3-27.5)
Complete responsePartial 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
EEstrogen(E)
Estrogen receptor
(ER)
Aromatase
AAndrogen(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
AKTmTOR
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
1. Bachelot T et al. J Clin Oncol. 2012;30:2718-2724; 2. Bedard PL et al. Breast Cancer Res Treat. 2008;108:307-317.
Primary Resistance to Endocrine Therapy in ER+BC
ER
Gene expression
E
EEstrogen
(E)
Estrogen receptor
(ER)
Aromatase
AAndrogen(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 ERαPost-translational modification of ERαExpression of ER cofactors
MYC amplification and overexpression
Cyclin D1 amplification or expression
PI3K
AKTmTOR
MAPK
RTK
Receptor tyrosine kinases(RTK)
Ras
1. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724; 2. Bedard PL, et al. Breast Cancer Res Treat. 2008;108(3):307-317
Everolimus in Hormone-refractory MBCTAM 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
0.00.10.20.30.40.50.60.70.80.91.0
Prob
abilit
y of
sur
viva
l
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28Months
Time (weeks)
HR = 0.36 (95% CI: 0.27–0.47)
EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months
Log rank P value = 3.3 x 10 -15
0 126 18 24 30 36 48 6042 54 7266 78
80
60
40
20
100
0
Prob
abilit
y of
Eve
nt (%
)
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: PFS
Presented at: San Antonio Breast Cancer Symposium, December 6-10, 2016
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 6Activity Slides
MANTA Study Design
Fulvestrant + Vistusertib(intermittent schedule; 2d on 5d off)
Fulvestrant + Vistusertib(intermittent schedule; 2d on 5d off)
Fulvestrant + EverolimusFulvestrant + 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
• 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 + Vistusertib(Continuous daily schedule)
FulvestrantFulvestrant
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 orally, once daily, continuous schedule• Vistusertib (continuous): 50 mg orally, twice daily, continuous schedule• Vistusertib (intermittent): 125 mg orally, 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
Prog
ress
ion-
free
Surv
ival
(%)
0 30Time (months)
12 24186
Number at risk
F+E 64 45 26 8 2 0F 66 29 14 6 1 0
F+VcontF+Vint
10195
5448
1721
68
34
00
CI = confidence interval; ITT = intent-to-treat; mths = months; PFS = progression-free survivalF = 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 + Vistusertibcont 7.6 (5.9-9.4)
Fulvestrant + Vistusertibint 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
Ribociclib + Letrozolen = 334
Placebo + Letrozolen = 330
n (%)Any
GradeGrade
3Grade
4Any
GradeGrade
3Grade
4
Total331
(99.1)232
(69.5)56
(16.8)322
(97.6)117
(35.5)6 (1.8)
Neutropenia214
(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 + Letrozolen = 444
Placebo + Letrozolen =222
n (%)Any
GradeGrade
3Grade
4Any
GradeGrade
3Grade
4
Total439
(98.9)276
(62.2)60
(13.5)212
(95.5)49
(22.1)5
(2.3)
Neutropenia353
(79.5)249
(56.1)46
(10.4)14
(6.3)2
(0.9)1
(0.5)
Leukopenia173
(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 (%) All G3 G4 All G3 G4Any 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) 0 23 (10.3) 4 (1.8) 0
Headache 89 (20.2) 3 (0.7) - 34 (15.2) 1 (0.4) -
Placebo + Fulvestrant
n = 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
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TEAE (Safety Population) SWISH Study
• Phase II single-arm trial evaluated prophylaxis with steroid mouthwash on everolimus-associated stomatitis
• Mouthwash: 10ml with dexamethasone 0.5mg/5mL (swish for 2-mins and spit) QID for 8 to 16 weeks started day 1 of exemestane and everolimus
• 92 patients enrolled with 85 evaluable
Rugo HS et al. Lancet Oncol. 2017;18:654-662.
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 7Activity Slides
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 Symptoms Management 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 everolimusat 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
24.8
14.5
9.2
3.87.8
3.2
8.64.5
0
5
10
15
20
25
30
CDKi+
LET
LET EXE TAMEVE +
TAM
EVE +
EXE
CDKi+
FULV
FULV
PFS,
mon
ths
LET +/- CDK4/6iLET +/- CDK4/6i FULV +/- CDK4/6iFULV +/- CDK4/6i EXE +/- EVEEXE +/- EVE TAM +/- EVETAM +/- EVE
BELLE 2: Addition of Buparlisib (Pan-PI3K Inhibitor) to Fulvestrant in Hormone-resistant MBC
CI = confidence interval; HR - hazard ratio; OS = overall survival; PFS = progression-free survival.
Full Population (N=1047)
Buparlisib + Fulvestrant
n=576
Placebo + Fulvestrant
n=571
Median 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-sidedP value
<0.001
Prob
abilit
y of
Pr
ogre
ssio
n-fre
e Su
rviv
al, %
Time (Months)
100
60
0
80
40
20
0 4 8 14 182 6 10 12 16 20 26 3022 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 82 6 10 12 14 16 18 20 22 24 26Time, Months
Prob
abilit
y of
Pr
ogre
ssio
n-fre
e Su
rviv
al, %
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.
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 8Activity Slides
• ER+/HER2- locally advanced or metastatic BC
• Postmenopausal • Recurrence or progression during
or after aromatase inhibitor
SANDPIPERPhase 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.
2nd line metastatic therapy or greater
Neoadjuvant
Ongoing Trials α-specific PI3K inhibitors
NCT02077933Phase I alpelisib +everolimus
+/- exemestane
NCT02437318 (SOLAR-1)Phase III fulvestrant +/-
alpelisib
NCT02340221 (Sandpiper)Phase III Fulvestrant +/-
Taselisib
NCT01923168 (Neo-Orb)Phase II Letrozole +/- Alpelisib or
Buparlisib
NCT02273973 (Lorelei)Phase II Letrozole +/-
Taselisib
Ribociclib (LEE011)Palbociclib (PD-0332991)Abemaciclib (LY2835219)
PI3K
AKT
mTOR
CCND1CDK4/6
pRb
E2F
Cell survivalProliferation
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 + RibociclibPhase Ib/II Study of Postmenopausal Women with AI-resistant ER+ MBC1
Letrozole + Alpelisib + RibociclibPhase Ib Study of Postmenopausal Women with ER+ MBC2
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 FGFRCompleted 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
CompletedHas 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
Activenot 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
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 9Activity Slides
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+ BC3,4
• In ER+ mBC resistant to endocrine therapy, total mutational burden increases5, 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
1Emens et al. Presented at: American Association for Cancer Research (AACR) 2015. 2Nanda et al. Presented at: AACR 2015. 3Dirix et al. JAVELIN trial. Presented at: SABCS 2015. 4Rugo et al KEYNOTE-028 trial. Prsented at: SABCS 2015. 5Lefebvre 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 plusEntinostat
Exemestane plusPlacebo
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 ([email protected]) 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
L869RL755S
G727AR143G S653C R1153LP1074L
Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2- Breast Cancer
©2018 Rockpointe Oncology 10Activity Slides
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 PCRIn the Randomized Phase III SoFEA Study
ESR1 Mutations in PALOMA-3
Presented by 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.Net
• A copy has been provided with your syllabus
• Excellent tool to provide patients
• Can 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 cancer
• But, 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…