ExpressPoints: Sequencing Treatment and

Overcoming Resistance in HR-Positive/HER2-

Negative ABC

Supported by an educational grant from Lilly.

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Faculty
Sara Hurvitz, MD, FACP
Associate Professor of Medicine
Director, Breast Oncology Program
Division of Hematology-Oncology
Department of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
Sara Tolaney, MD, MPH
Assistant Professor of Medicine
Harvard Medical School
Associate Director
Susan F. Smith Center for Women’s
Cancer
Director of Clinical Trials, Breast
Oncology
Director of Breast Immunotherapy
Clinical Research
Senior Physician
Breast Oncology Program
Dana-Farber Cancer Institute
Boston, Massachusetts
Faculty Disclosures
Sara Hurvitz, MD, FACP, has disclosed that she has received funds for research
support from Ambrx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian,
Daiichi Sankyo, Dignitana, Genentech, GlaxoSmithKline, Lilly, Macrogenics,
Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Roche, and
Seattle Genetics.
Sara Tolaney, MD, MPH, has disclosed that she has received funds for research
support (paid to her institution) from AstraZeneca, Bristol-Myers Squibb, Cyclacel,
Eisai, Exelixis, Genentech, Immunomedics, Lilly, Merck, Nanostring, Nektar,
Novartis, Odonate, Pfizer, and Sanofi and consulting fees from AbbVie,
AstraZeneca, Athenex, Bristol-Myers Squibb, Celldex, Daiichi Sankyo, Eisai, G1
Therapeutics, Genentech, Immunomedics, Lilly, Nanostring, Nektar, Novartis,
Odonate, Paxman, Pfizer, Puma, Sanofi, Seattle Genetics, and Silverback.
 Targeted and Antiestrogen Therapies to Overcome
Resistance in HR+ ABC: FDA-Approved Agents
EGFR E AI  ~ 30% of HR+ MBCs are de
HER2 Nonsteroidal AIs:
Anastrozole
novo resistant to ET, with
Letrozole
Steroidal AI:
most developing acquired
P P PI3K Inhibitors
Exemestane resistance
Alpelisib

RAS PI3K
E
 Mechanisms of resistance
ER may include loss/alteration
Raf
MEK
Akt
E
ER-α
Downregulator
Fulvestrant of ER expression;
mTOR Inhibitors
Everolimus MAPK
overexpression/activation
mTOR Selective ER
modulators
of GF receptors; or activation
CDK4/6 Inhibitors
Palbociclib
Tamoxifen of downstream signal
Toremifene
Abemaciclib transduction pathways
Ribociclib Cell E E ER target gene
cycle ER-α ER-α transcription Cell cycle regulation
DNA replication
Transcription Cellular differentiation
silencing Apoptosis
Angiogenesis
Brufsky. Oncologist. 2018;23:528. AlFakeeh. Curr Oncol. 2018;25:S18. Slide credit: clinicaloptions.com
 CDK4/6 Inhibition in HR+/HER2- ABC: Phase III Trials
Parameter PALOMA-2[1,2] MONALEESA-2[3,4] MONARCH-3[5,6] MONALEESA-3†[7-9] MONALEESA-7[10-12]
CDK4/6i Palbociclib Ribociclib Abemaciclib Ribociclib Ribociclib
Endocrine Letrozole Letrozole Letrozole Fulvestrant Tamoxifen, letrozole, or
partner or anastrozole anastrozole

1L mOS, mos -- -- -- NR vs 40.0 NR vs 40.9

Setting  HR -- -- -- 0.724; P = .00455 0.712; P = .00973
mPFS, mos 27.6 vs 14.5 25.3 vs 16.0 28.18 vs 14.76 33.6 vs 19.2 23.8 vs 13.0
 HR 0.563 0.568 0.54 0.55‡ 0.55
ORR, % 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7† 41 vs 30

Parameter PALOMA-3[13,14] MONARCH-2[15] MONALEESA-3†[7,8]

CDK4/6 inhibitor Palbociclib Abemaciclib Ribociclib

2L Endocrine partner Fulvestrant Fulvestrant Fulvestrant

Setting mPFS, mos 11.2 vs 4.6 16.9 vs 9.3 14.6 vs 9.1
 HR 0.50 0.536 0.57
ORR, % 25 vs 11 48.1 vs 21.3 32.4 vs 21.5†
*1st line ET; up to 1 prior CT line permitted in advanced setting (14% had received CT). †Includes 1st and 2nd line. ‡Descriptive analysis.
1. Finn. NEJM. 2016;375:1925. 2. Rugo. Breast Cancer Res Treat. 2019;174:719. 3. Hortobagyi. NEJM. 2016;375:1738. 4. Hortobagyi.
Ann Oncol. 2018;29:1541. 5. Goetz. JCO. 2017;35:3638. 6. Johnston. NPJ Breast Cancer. 2019;5:5. 7. Slamon. JCO. 2018;36:2465.
8. Slamon. NEJM. 2020;382:514. 9. Slamon. ESMO 2019. Abstr LBA7_PR. 10. Tripathy. Lancet Oncol. 2018;19:904. 11. Hurvitz. ASCO
2019. Abstr LBA1008. 12. Im. NEJM. 2019;381:307. 13. Cristofanilli. Lancet Oncol 2016;17:425. 14. Turner. NEJM. 2018;379:1926.
15. Sledge. JAMA Oncol. 2020;6:116 Slide credit: clinicaloptions.com
 Key AEs With CDK4/6 Inhibitors:
Monitoring and Prevention
Diarrhea Hepatobiliary QT Prolongation Neutropenia VTE ILD/
Toxicity Pneumonitis
Abemaciclib Abemaciclib Abemaciclib Abemaciclib Abemaciclib
Palbociclib Palbociclib Palbociclib
Ribociclib Ribociclib Ribociclib Ribociclib Ribociclib
CBC before starting
treatment, then:
LFTs before starting  Abemaciclib, Q2W
Antidiarrheal therapy tx, Q2W x 2 mos, ECG before cycle 1, x 2 mos,
QM x 2 mos, then Monitor for
then: Day 14 of cycle 1,
as indicated pulmonary
Increase oral start of cycle 2, then Monitor for signs and
symptoms indicative
hydration  Abemaciclib, as as indicated  Palbociclib, Days 1 symptoms of
of ILD or
indicated and 15 of cycles 1- thrombosis or
pneumonitis
Notify healthcare Electrolytes at start 2, then as pulmonary embolism
(eg, hypoxia, cough,
provider  Ribociclib, at start of cycle x 6 cycles, indicated
dyspnea)
then as indicated
of cycle x 4 cycles  Ribociclib, Q2W x
2 cycles, start of
next 4 cycles, then
as indicated

Abemaciclib PI. Palbociclib PI. Ribociclib PI. Slide credit: clinicaloptions.com

 Efficacy and Safety Considerations With mTOR Inhibitor
Everolimus
BOLERO-2: PFS (Locally Assessed)
Events, Median PFS, Wk 8 Stomatitis, % BOLERO-2 (N = 482) SWISH (N = 85)
n/N Mos
1.0 No stomatitis 38.8 78.8
EVE + EXE 310/485 7.8
Grade 1 33.8 18.8
Probability of PFS

0.8 PBO + EXE 200/239 3.2

HR: 0.45 (95% CI: 0.38-0.54; P < .0001) Grade 2 20.1 2.4
0.6 Grade 3 7.3 0
0.4 Grade 4 0 0
0.2  Phase II SWISH trial: steroid mouthwash‡
+ Censored
0 essentially eliminated stomatitis in
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 postmenopausal patients with HR+/HER2-
Mos MBC receiving everolimus + exemestane
Patients at Risk, n
EVE + EVE 485 394 318 236 194 147 99 57 42 23 13 10 4 1 0
PBO + EVE 239 146 103 61 42 27 17 9 6 2 1 1 0 0 0 ‒ Gr ≥ 2 stomatitis was 2.4% by 8 wks in SWISH
vs 27.4% by 8 wks in BOLERO-2 (primary
 Improved PFS with mTOR inhibition regardless of endpoint) and 33% over total study duration
PIK3CA mutation; similar results with tamoxifen +
fulvestrant
‡
Dosing: 10 mL alcohol-free dexamethasone 0.5 mg per 5 mL oral
solution. Swish for 2 min then spit. Repeat 4x per day for 8 wks.
Yardley. Adv Ther. 2013;30:870. Baselga. NEJM. 2012;366:520. Slide credit: clinicaloptions.com
 Phase III SOLAR-1 Trial: Locally Assessed PFS With PI3Kα
Inhibitor Alpelisib in PIK3CA-Mutant Cohort
Alpelisib + FULV Placebo + FULV  In phase II BYLieve
(n = 169) (n = 172)
100
PFS events, n (%) 103 (60.9) 129 (75.0)
trial cohort with
 Progression 99 (58.6) 120 (69.8) PIK3CA-mutant
80  Death 4 (2.4) 9 (5.2) HR+/HER2- ABC
 Censored
Probability of PFS

66 (39.1) 43 (25.0) after CDK4/6i + AI,

Median PFS (95% CI) 11.0 (7.5-14.5) 5.7 (3.7-7.4) alpelisib +
60
fulvestrant
associated with:
40
‒ mPFS: 7.3 mos
20 ‒ ORR: 21.0%
HR: 0.65 (95% CI: 0.50-0.85; P = .00065)
Data cutoff: June 12, 2018
0
0 1 2 3 4 5 6 7 8 9 10 1112 13 141516 1718 19202122 23242526 2728 293031
Mos
Patients at Risk, n
Alpelisib + FULV 169 158 145141 123 113 97 95 85 82 75 71 62 54 50 43 39 32 30 27 17 16 14 5 5 4 3 3 1 1 1 0
Placebo + FULV 172 167 120111 89 88 80 77 67 66 58 54 48 41 37 29 29 21 20 19 14 13 9 3 3 2 2 2 0 0 0 0

André. NEJM. 2019;380:1929. Andre. ESMO 2018. Abstr LBA3_PR. Slide credit: clinicaloptions.com
10

Before Initiating Alpelisib: Considerations

Verify pregnancy
status in women of
reproductive potential
prior to initiating
alpelisib
All Patients[1]
Consider an antihistamine
when initiating alpelisib
• Prophylactic antihistamines
administered prior to rash onset
on SOLAR-1 decreased incidence
and severity of rash
Baseline glucose
Assess FPG and A1C before
initiating treatment with
alpelisib
• Optimize blood glucose
before initiating alpelisib
Plan for glucose monitoring after
treatment initiation
Monitor fasting glucose:
• At least weekly during the first 2 wks
• Then at least every 4 wks and as clinically
indicated
Monitor A1C:
• Every 3 mos and as clinically indicated

Hyperglycemia Monitoring Schedule[1,2]

e 5 9
Additional monitoring as clinically indicated elin y 1 y1 y2
s
Ba D
a Da Da
Fulvestrant dose
FPG Fasting glucose
A1C Mo 1 Mo 2 Mo 3

Prediabetic/Diabetic Patients*[1]
Closely monitor glucose, may require intensified Counsel patients on lifestyle changes related to exercise and dietary
antihyperglycemic treatment intake, as appropriate
*SOLAR-1 excluded patients with type 1 diabetes or uncontrolled type 2 diabetes. At baseline in alpelisib arm, 56% of patients were
prediabetic (FPG 5.6 to < 7.0 mmol/L and A1C 5.7% to < 6.5%) and 4% were diabetic (FPG ≥ 7.0 mmol/L or A1C ≥ 6.5%). [2,3]

1. Alpelisib PI. 2. Rugo. Ann Oncol. 2020;[Epub]. 3. André. NEJM. 2019;380:1929. Slide credit: clinicaloptions.com
 Approach to Therapy for HR+/HER2- MBC:
Move to Personalization
1L[1-4] 2L[1] 3L 4L/5L[1] 4L+[1]

AI + CDK4/6i Fulvestrant ± Exemestane + Taxane or

everolimus[8] capecitabine Eribulin
everolimus
Fulvestrant + CDK4/6i BRCAm: olaparib or
Exemestane + talazoparib[9,10]
everolimus
PIK3CAm:
fulvestrant +
alpelisib[5]
HER2 low: trastuzumab Sacituzumab
deruxtecan (DS8201a) govitecan
ESR1m: SERD (+ CDK4/6i)[6,7] [11]
(IMMU-132)[13]

HER2m: neratinib[12]

1. Cardoso. Ann Oncol. 2018;29:1634. 2. Abemaciclib PI. 3. Palbociclib PI. 4. Ribociclib PI. 5. Alpelisib PI. 6. Fribbens. JCO.
2016;34:2961. 7. Bardia. SABCS 2017. Abstr PD5-08. 8. Everolimus PI. 9. Olaparib PI. 10. Talazoparib PI. 11. Modi. JCO.
2020;38:1887. 12. Smyth. Cancer Discov. 2020;10:198. 13. Bardia. ASCO 2018. Abstr 1004. Slide credit: clinicaloptions.com
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