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Things about advanced breast cancer that keep us up at night

Expert: Prof Hope S. Rugo, University of California San Francisco, San Francisco, USA
Discussant: Dr Olivia Pagani, Riviera-Chablais Hospital, Rennaz, Switzerland

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e-Sessions via e-ESO.net | 21 The European School of Oncology 1

Things about advanced breast
cancer that keep us up at night
Hope S Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
University of California, San Francisco Medical Center
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California
Disclosures
A few things about ABC that keep us up at night
 KEYNOTE-355 Study Design (NCT02819518)
OS: PD-L1 CPS ≥10
Key Eligibility Criteria HR P-value
• Age ≥18 years n/N Events (95% CI) (one-sided)
• Central determination of TNBC and Pembrolizumabb + Chemotherapyc
PD-L1 expressiona Pembro + Chemo 155/220 70.5% 0.73 0.0093a
• Previously untreated locally recurrent (0.55-0.95)
inoperable or metastatic TNBC
• De novo metastasis or completion of R
2:1
PD-L1 CPS ≥10 Progressive
diseasee/cessation
Placebo + Chemo 84/103 81.6%
treatment with curative intent ≥6 months
prior to first disease recurrence
of study therapy 100
58.3%
• ECOG performance status 0 or 1
90 44.7%
• Life expectancy ≥12 weeks from Placebo d + Chemotherapyc
randomization
• Adequate organ function
80
• No systemic steroids
70
6.9 month increase in OS
• No active CNS metastases
Stratification Factors:
• No active autoimmune disease • Chemotherapy on study (taxane or gemcitabine-carboplatin)
• PD-L1 tumor expression (CPS ≥1 or CPS <1)f 60

OS, %
• Prior treatment with same class chemotherapy in the 23.0 months
50 16.1 months
neoadjuvant or adjuvant setting (yes or no)
PFS: PD-L1 CPS ≥10 40
30
20
10
Prespecified P value boundary of
0
0.00411 met
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Time, months
38% of pts No. at risk
220214193171154139127116105 91 84 78 73 59 43 31 17 2 0
103 98 91 77 66 55 46 39 35 30 25 22 22 17 12 8 6 2 0
Cortes et al, Lancet 2020; Rugo et al , ESMO 2021

Prespecified P value boundary of

 Impact of PD-L1 CPS Subgroups on OS and PFS
Overall Survival Progression Free Survival
Median OS (mo) Median PFS (mo)
Patients Pembro + Patients Placebo Hazard Ratio Patients Pembro + Patients Placebo Hazard Ratio
Subgroup n Chemo n + Chemo (95% CI) Subgroup n Chemo n + Chemo (95% CI)

Overall 566 17.2 281 15.5 0.89 (0.76 to 1.05) Overall 566 7.5 281 5.6 0.82 (0.70 to 0.98)

PD-L1 CPS <1 141 16.2 70 14.7 0.97 (0.72 to 1.32) PD-L1 CPS <1 141 6.3 70 6.2 1.09 (0.78 to 1.52)

PD-L1 CPS 1-9 205 13.9 108 15.5 1.09 (0.85 to 1.40) PD-L1 CPS 1-9 205 5.7 108 5.6 0.85 (0.65 to 1.11)

PD-L1 CPS 10-19 80 20.3 39 17.6 0.71 (0.46 to 1.09) PD-L1 CPS 10-19 80 9.9 39 7.6 0.70 (0.44 to 1.09)

PD-L1 CPS ≥20 140 24.0 64 15.6 0.72 (0.51 to 1.01) PD-L1 CPS ≥20 140 9.2 64 5.4 0.62 (0.44 to 0.88)

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 2.0

Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Favors Favors Favors Favors

Pembro + Chemo Placebo + Chemo
Pembro + Chemo Placebo + Chemo
 Immune-Mediated AEs
20

18

16

14
Incidence, %

12

10

Immune-
a Basedon a list of terms prespecified by the sponsor and included regardless of attribution to study treatment or immune relatednes s by the investigator; related terms included.
Data cutoff: June 15, 2021.
 IMPASSION 130: PD-L1 IC status by SP142 predicts PFS and OS
benefit with atezolizumab + nab-paclitaxel1,2
(41% positive by SP142)

A + nP, atezolizumab + nab-paclitaxel; HR, hazard ratio; ITT, intention to treat; OS, overall survival; P + nP, placebo + nab-paclitaxel; PFS, progression-free survival.
PD-L1 IC+: PD-
 IMpassion 130: OS in the PD-L1 IC+ population
PD-L1 IC+ population
A + nP (n = 185) P + nP (n = 184)
OS events, n (%) 120 (65) 139 (76)
Stratified HR
0.67 (0.53, 0.86)a
Overall survival

(95% CI)

3-year OS: 36% Subset Analysis for OS (HR)

Median OS (95% CI):

17.9 mo 25.4 mo
3-year OS: 22%
(13.6, 20.3) (19.6, 30.7)

No. at risk
Time (months)
(PD-L1+ population):
A + nP
P + nP

Data cutoff, 14 April 2020. NE, not estimable. Emens et al: Ann Oncol 2021
aP value not displayed since OS in the PD-L1+ population was not formally tested due to the hierarchical study design. IMpassion130 Final OS. 9
 Immunotherapy: First-Line Rx for mTNBC
IMPASSION 131 IMPASSION 130 KEYNOTE 355
N (PD-L1+) 943 (292, 45%) 902 (369, 41%) 847 (332, 38%)
>1% >1% CPS>10
Randomization 2:1 1:1 2:1
and Treatment Paclitaxel 90 mg/m2 nab-Paclitaxel 100 Pac/nab/gem+carbo
Atezolizumab mg/m2 Pembrolizumab
Atezolizumab
de novo 28-30% ~37% (no chemo) 30%
Prior taxane 51-53% 51% 45%
PFS in PD-L1+ 5.7 6 mo; HR 0.82 5 7.5 mo; HR 0.62 5.6 9.7 mo; HR 0.65
P=0.2 P<0.0001 P=0.0012
FDA approved 7/21
OS benefit No YES YES
Miles et al, Ann Oncol 2021; Schmid et al, NEJM 2018 & Emens et al, Ann Oncol 2021; Cortes et al, Lancet 2020; Rugo et al, ESMO 2021
What are the Questions for Metastatic CPI?
Amplifying the Immune Response TONIC Trial: induction
followed by nivolumab
Voorwerk et al, Nat Medicine 2019

TBCRC 047:
InCITe Trial Design
R R
Metastatic TNBC A Binimetinib Binimetinib + Avelumab +
• Measurable disease E
N Liposomal doxorubicin
• No more than 2 prior G
I D Sacituzumab
metastatic lines of Sacituzumab govitecan +
chemotherapy S O govitecan
M Avelumab
• Known PD-L1 status T
• Prior IO allowed E I
Z Liposomal Avelumab +
R Liposomal doxorubicin
E doxorubicin

*Novel agent 1: Binimetinib, a MEK inhibitor (oral)

#Novel agent 2: Sacituzumab govitecan 1 Cycle=4 weeks
Avelumab: PD-L1 inhibitor, IV every 2 wks 15 day lead-in Tumor assessments & PRO q 8 wks
Liposomal doxorubicin: IV every 4 wks

Tumor biopsy Tumor biopsy Blood collection (at

Blood collection Blood collection 8 weeks and at PD)
*Safety combination data from MiLO trial
#Safety combination data from several ongoing trials
PI : Hope S. Rugo
KEYNOTE-028: Safety and Antitumor Activity of Pembrolizumab in
Patients with ER+/HER2- Advanced Breast

Rugo H S et al. Clin Cancer Res; 24(12) June 15, 2018

A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Pembrolizumab Plus
Chemotherapy Versus Placebo Plus Chemotherapy for the Treatment of Chemotherapy-Candidate
Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-)
Locally Recurrent Inoperable or Metastatic Breast Cancer (KEYNOTE-B49)

Key eligibility criteria:

 ADCs: Sacituzumab Govitecan

Progression-Free Survival (BICR Analysis) Overall Survival

3.9 month improvement in PFS 5.4 month improvement in PFS

1.7 vs 5.6 mo 6.7 vs 12.1 mo

HR 0.46, p<0.0001 HR 0.48, p<0.0001
Newer ADCs for TNBC
ADC Target Trial Results Primary toxicites
Datopotamab Trop2 Phase 1 ORR: 43% (n=21) Stomatitis, rash
deruxtecan

Ladiratuzumab LIV1a Phase 2 ORR: 35% Neuropathy, neutropenia

vedotin (n=63)

Trastuzumab HER2 Phase 1 ORR: 14% Nausea, pneumonitis

deruxtecan (n=7, HER2 low)
U3-1402 HER3 Phase 1 ORR: 16% Nausea, cytopenias,
(n=31, HER3 high pneumonitis

Phase III trials New directions: Combinations with immunotherapy

Trastuzumab deruxtecan: HER2 low completed (DESTINY Sacituzumab (pembrolizumab, avelumab)
Breast04)
Trastuzumab deruxtecan (durvalumab (Begonia trial), pembrolizumab)
Dato-DXd: phase 3 TROPION-Breast01 in HR+ disease, TN trial
Ladiratuzumab vedotin (pembrolizumab)
planned

Krop SABCS 2021; Modi et al, SABCS 2017; Han et al, SABCS 2019; Modi et al, JCO 2020; Krop et al, SABCS 2020
Datopotamab Deruxtecan (Dato-DXd): Phase 1 TROPION-PanTumor01 Study
Prevalence of HER2 Low HER2 neg HR pos Triple Negative

HER2 IHC examples

HER2+
N=1576 N=1137 N=437

IHC 0 IHC 1+ IHC 2+not amplified

HER2-low

HER2-
N=673 N=701 N=325

Schettini et al, NPJ Breast Cancer 2021

Proportion of HER2-low higher in HR+ BC (65%) compared to TNBC (37%)
DESTINY-Breast04 HER2-low (IHC 1+ or IHC2+/ISH-)
unresectable or metastatic BC
Phase 3
Trastuzumab deruxtecan vs TPC
Completed accrual
Brain metastases: An unmet clinical need
Advances in Adjuvant Therapy: No Impact on Frequency of
CNS as 1st Site of Recurrence in HER2+ Disease

Von Minckwitz et al, NEJM 2019

 Chemo combinations with some efficacy data
Chemo regimen Pts (Breast/Other) ORR/ TTP/PFS OS Author/ Year
Cisplatin/Etoposide 116 (56/60) 38% ORR 31 wks Franciosi 1999
Cisplatin/TMZ 32 (15/17) 40% ORR / 2.9 mo TTP 5.5 mo Christodoulou 2005
Capecitabine/TMZ 24 18% ORR/ 12 wk TTP NR Rivera 2006
Irinotecan/Iniparib 34 (All TNBC) 12% ORR/27% CBR/ 2.1 mo TTP 7.8 mo Anders 2014
Bevacizumab/Cis/Etoposide 35 77% CNS OR/ 7.3 mo CNS PFS 10.5 mo Lu 2015
Irinotecan/TMZ 30 (8 with LMD) 7% ORR/23% CBR/2.3 mo TTP 4.9 mo Melisko 2019
Liposomal Irinotecan (MM398) 10 30% NR Anders 2020
HER2 Targeted therapies
Trastuzumab-emtansine 10 30% ORR/ 50% 6mo CBR/ 5 mo PFS NR Bartsch 2015
Vinorelbine/trastuzumab/ 32 (safety)/26 4% CNS ORR/27% CBR/ 3.9 mo TTP 12.2 mo Anders 2018
everolimus efficacy
Cape/lapatinib/everolimus 19 28% CNS ORR/ 6.2 mo PFS 24.2 mo Hurvitz 2018
NR= Not reported
A Phase 2 Study of Abemaciclib in Patients With Brain Metastases
Secondary to Hormone-Receptor-Positive Breast Cancer
TBCRC22 Cohort 2
HER2CLIMB Primary and Updated Analysis Results
HER2 Climb: Tucatinib Improves PFS and OS in Patients with Brain Metastases
Events HR
N=291 (95% CI) P Value Events HR
N=291 (95% CI) P Value
TUC+Tras+Cape 106/198 0.48 <0.00001 TUC+Tras+Cape 68/ 198 0.58 0.005
(0.34, 0.69) Pbo+Tras+Cape 46/ 93 (0.40, 0.85)
Pbo+Tras+Cape 51/93
60% 70.1%

Median
Median

46.7%
34%
25%

0%

Risk of death was reduced by

Risk of progression or death in 42% in patients with brain
patients with brain metastases was metastases
reduced by 52% in the total
population One-year OS (95% CI):
One-year PFS (95% CI): TUC+Tras+Cape Pbo+Tras+Cape
TUC+Tras+Cape Pbo+Tras+Cape 70.1% 46.7%
25% 0% (62.1, 76.7) (33.9, 58.4)
(17, 34)
Median OS (95% CI):
Median PFS (95% CI):
18.1 months 12.0 months
7.6 months 5.4 months
(6.2, 9.5) (4.1, 5.7) Lin et al, JCO 2020 (15.5, NE) (11.2, 15.2)
DESTINY Breast03: Trastuzumab deruxtecan vs T-DM1
PFS curves for patients w/ and w/o brain mets

Intracranial response rates in pts with brain mets:

63.9% with T-DXd vs 33.4% with T-DM1
History of BM, n (%)
Yes | No 62 (23.8) | 199 (76.2) 52 (19.8) | 211 (80.2)
BM at baseline,b n (%)
Hurvitz S et al. SABCS 2021
Yes | No 43 (16.5) | 218 (83.5) 39 (14.8) | 224 (85.2)
 Intracranial Response per BICR using RECIST 1.1
100
T-DXd (n = 21)
80
Best % Change in Sum of Diameters from Baseline

60
T-DXd T-DM1
40
(n = 36) (n = 36)
20

0
Best Overall Response, n (%)a
-20

-40 CR 10 (27.8) 1 (2.8)

-60

-80 PR 13 (36.1) 11 (30.6)

-100
Non-CR/non-PD 6 (16.7) 7 (19.4)
100
T-DM1 (n = 23) SD 4 (11.1) 7 (19.4)
80

60 PD 1 (2.8) 8 (22.2)
40
Not evaluable 0 1 (2.8)
20

0 Missing 2 (5.6) 1 (2.8)

-20

-40

-60
CR, complete response; DCR, disease control rate; mDOR, median duration of response; PD, progressive disease; PR,
-80 partial response; SD, stable disease; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.
Table includes target and non-target lesions. Only patients with target lesion assessments are eligible for inclusion in
-100 waterfall.
Red line at 20% indicates progressive disease; black line at -30% indicates partial response.
aDenominator for percentages is the number of subjects in the full analysis set with brain metastases tumor assessment

Hurvitz S et al. SABCS 2021

 Primary endpoint: CNS Response Rate
RANO response criteria for brain metastases
Criterion Complete Partial Stable Progressive
Response Response Disease Disease
Target Lesions None > 30% decrease < 30% decrease > 20% increase in
in sum LD relative relative to sum LD relative to
to baseline baseline but nadir
<20% increase
in sum LD
relative to nadir
Non
Radiation Toxicity: Preventing Cognitive Decline
Leptomeningeal disease
Diagnosis and treatment
Emerging Therapies
Sequencing Therapy
Sequencing Therapy for Metastatic TNBC: Not enough options for most
First line Second line
*Pembrolizumab + nab-
paclitaxel or paclitaxel*

BRCA
PD-L1+ mutation PARPi

Novel ADCs
Pembrolizumab +
Metastatic TNBC gemcitabine/carboplatin Sacituzumab
Govitecan Chemotherapy
Chemotherapy
Checkpoint
PD-L1- inhibitor
Clinical trials

Clinical trials
PARPi

*Pembrolizumab (CPS) or atezolizumab ex US (SP142), nab-paclitaxel only)

PARPi: PARP inhibitor (olaparib, talazoparib)

Always consider clinical trials at each decision point

 Algorithm for Endocrine Treatment and Targeted Therapy for HR-positive, HER2-negative Metastatic Breast Cancer
Postmenopausal patients, and male
patients, with HR-positive, HER2-
negative, advanced or metastatic
breast cancer
Treated with Adjuvant
Aromatase Inhibitor?
No
Aromatase Inhibitor + CDK 4/6
Inhibitor
as first-line therapy
Germline BRCA 1/2 Mutation
Notes.
*Patients receiving alpelisib should have laboratory and symptom monitoring weekly for the first four weeks of therapy in order to avoid serious toxicity.
Abbreviations.
CDK, cyclin-dependent kinase; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PARP, poly-ADP-ribose polymerase
Fulvestrant + CDK 4/6 Inhibitor
Yes
as first-line therapy
PIK3CA Mutation?
No
Fulvestrant ± Everolimus
as second-line therapy
Oral PARP inhibitor as monotherapy
Yes may be offered in the first- through
third- line setting
Tamoxifen, Aromatase Inhibitor, or
Fulvestrant
PIK3CA Mutation? Yes
+ Alpelisib*
as second-line therapy Tamoxifen, aromatase inhibitor, or
fulvestrant (with targeted therapy if
No not already given) or chemotherapy
as third-line therapy
Tamoxifen, Aromatase Inhibitor, or
Fulvestrant
± Everolimus
as second-line therapy
Fulvestrant + Alpelisib*
Yes as second-line therapy
Chemotherapy or any one of the
following (with targeted therapy if not
already given): tamoxifen, aromatase
inhibitor, or fulvestrant
as third-line therapy
 HR+HER2- ABC: Remarkable Progress Leads to Changing Paradigms
High Endocrine Moderate Endocrine Poor Endocrine
Sensitivity Sensitivity Sensitivity
Endocrine therapy naove* Progression between 2-3 yrs from Progression within 1 yrs
Progression > 1y after adjuvant ET start or < 1y from end of adjuvant ET from start of adjuvant AI

NSAI + CDK4/6i Fulvestrant + CDK4/6i Fulvestrant +

CDK4/6i Fulvestrant + ChemoRx
CDK4/6i
PIK3CA WT PIK3CA mut PIK3CA WT PIK3CA mut
PIK3CA WT PIK3CA mut
Fulvestrant Fulvestrant Exe-Eve
+ alpelisib NSAI +
alpelisib Exemestane AI +
+ everolimus alpelisib
Exemestane +
everolimus

*De novo stage IV disease appears to be enriched in relative endocrine resistant disease
 Post-ESMO 2021 Approach to Therapy for Metastatic HER2+ BC:
Current Approach for Metastatic HER2+ Breast Cancer

1st line Taxane + trastuzumab + pertuzumab*#

ET +TP maintenance Active CNS disease

2nd line Tucatinib
Trastuzumab Deruxtecan
Trastuzumab/capecitabine

Trastuzumab Deruxtecan
3rd line Tucatinib/Trastuzumab/
T-DM1 capecitabine
4th line T-DM1

5th line+ Margetuximab + chemotherapy

or
Neratinib + capecitabine (for CNS benefits)
or
Trastuzumab + lapatinib or other chemotherapies
Adapted from Modi, ESMO 2021
*AI+TP in select cases and for maintenance in ER+ disease; # endocrine Tx + HER2 therapy at clinically appropriate points for ER+ MBC
FINANCIAL TOXICITY
FINANCIAL COSTS & BURDEN
Thank you!