TREATMENT OF “METASTATIC” TNBC

ESMO VIRTUAL PRECEPTORSHIP VIRTUAL

PRECEPTORSHIP
ON BREAST CANCER
10-11 February 2022

Rebecca Dent, MD FRCP (C)

Chairman and Senior Consultant, Division of Medical Oncology
National Cancer Center Singapore
Associate Professor, Duke-NUS Medical School
DECLARATION OF INTERESTS
Advisory/consultancy: AstraZeneca, Eisai, Lilly, MSD, Novartis, Pfizer,
and Roche

Travel, accommodations, and expenses: AstraZeneca, Eisai, Lilly,

MSD, Pfizer, and Roche

Rebecca Dent Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
 Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
Annals of Oncology 2021
Study 301: Eribulin vs Capecitabine in
Previously Treated LABC or MBC

Eribulin Mesylate 1.4 mg/m2

D1,8 q21d
≤3 prior chemo (n = 554)
(≤2 for advanced disease)
prior anthracycline & taxane
N = 1102 Capecitabine 1250 mg/m2 BD
D1-14 q21d
Stratified by geographical (n = 548)
region, HER2 status

Targeting EMT?
Kaufman PA et al, JCO 2015
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Study 301: Eribulin vs Capecitabine
Subgroup HR (95% CI) Eribulin Capecitabine
Median (months)
Overall 0.879 (0.770, 1.003) 15.9 14.5
HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative n=755 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative n=449 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes n=284 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

0.2 0.5 1.0 2 5

ITT population Favours Eribulin Favours Capecitabine
Twelves C et al, Breast Content
Cancer (Auckl) 2016.
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 TNT: Carboplatin vs Docetaxel in
Advanced TNBC or BRCA1/2+ Breast Cancer

Tutt A et al, Nature Med 2018

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TNT: ORR of Carboplatin vs Docetaxel in
Advanced TNBC or BRCA1/2+ Breast
Cancer Carboplatin
90 Docetaxel
80 Crossover
Response at Cycle 3 or 6 (%)
P = .03
70 68.0%
60
50 P = .44 P = .16
40 35.6% 36.6%
31.4% P = .73 33.3%
30 28.1%
22.8%25.6%
20
10
0
All Pts C→D D→C BRCA1/2 No BRCA1/2
(n = 376) Crossover* Mutation Mutation
(All pts; n = 182) (n = 43) (n = 273)
*Excludes those with no first progression or not starting crossover treatment.

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Chemotherapy options for metastatic TNBC

Other
Antimetabolite Platinum
Taxanes Anthracyclines Microtubule
s Agents
Inhibitors
●Paclitaxel ●Doxorubicin ●Capecitabine ●Vinorelbine ●Carboplatin
●Nab-paclitaxel ●Pegylated
liposomal
●Gemcitabine ●Eribulin ●Cisplatin Topoisomerase I inhibitor - ADC
●Docetaxel ●Ixabepilone
doxorubicin
●Epirubicin

Sequential single-agent chemotherapy is

the preferred approach for most patients
with metastatic TNBC

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 Treatment Algorithm Metastatic Triple Negative Breast Cancer
Positive Negative
BIOMARKER TESTING
IHC: PD-L1
Clinical Trial and
IHC:
Biomarker

PD-L1+ (SP142 and/or 22C3 assays) PD-L1– UNMET NEED Molecular Profiling

Molecular: gBRCA+ gBRCA+

PD-L1 +: nab-paclitaxel + atezolizumab gBRCA+: PARP inhibitor or platinum chemotherapy

or taxane, gem/carbo + pembrolizumab c
gBRCA-: Standard chemotherapy*
1L

(pending OS results
gBRCA+: PARP inhibitor or platinum chemotherapy (chemotherapy+ bevacizumab approved in some countries)

(no data on best approach if PD-L1 + and gBRCA + but IO not

approved beyond 1st line)

gBRCA+ : PARP inhibitor or platinum chemotherapy (if not gBRCA+ : PARP inhibitor or platinum chemotherapy (if not
given in 1L)
2L

given in 1L)

gBRCA-: Standard chemotherapy* gBRCA-: Standard chemotherapy*

Sacituzumab govitecan (if available)

3L+

*Standard chemotherapy:
taxane/platinum/eribulin/capecitabine/adriamycin/vinorelbine/CMF
(older non-standard: irinotecan/etoposide)
TMB high, MSI- H: pembrolizumab single agent Dent SOLTI 2020
Which PD-L1 test to order?

◆ USA – CPS score using 22C3 assay (as only pembrolizumab is now approved), CPS ≥10

◆ ex-USA – SP 142 (Atezolizumab) and/or CPS score using 22C3 assay (Pembrolizumab), depending on
country approval and reimbursement
What site should I test for PD-L1?

• Higher % of PD-L1 IC + primary 63.7% vs. metastastic 42.2%

• Lower positivity rates in liver (17.4%), skin (23.8%) and bone (16.7%)
metastasis
 PD-L1 status in primary vs metastatic tissues
PD-L1 status by
Efficacy in PD-L1 IC+ primary vs metastatic tissuea

PFS OS Primary tissue (62%) 44%

HR, 0.61 (95% CI: 0.47, 0.81) HR, 0.79 (95% CI: 0.57, 1.09) P = 0.014

Metastatic tissue (38%) 36%

Primary
Survival (%)

Survival (%)
0% 20% 40% 60%

PD-L1 IC+

Months Months
PD-L1 status by anatomical locationa
HR, 0.69 (95% CI: 0.46, 1.03) HR, 0.55 (95% CI: 0.32, 0.93)
Breast (64%) 43%
Metastatic

Lymph node (12%)

Survival (%)

Survival (%)

51%

Lung (6%) 43%

Liver (5%) 13%

Soft tissue (4%) 30%

Skin (2%) 48%

Months Months
Atezolizumab + nab-paclitaxel Other (6%) 36%
Placebo + nab-paclitaxel 0% 20% 40% 60%

▪ Median time of sample collection to randomization: 61 days PD-L1 IC+

12
 IMpassion130 study design
Key eligibility criteria
Atezolizumabb
• Histologically documented metastatic or + nab-paclitaxelc
inoperable, locally advanced TNBC Treatment until
R progression or
• No prior therapy for advanced TNBCa 1:1 Double-blind
– Prior chemotherapy including taxanes allowed in unacceptable
curative setting if treatment-free interval ≥ 12 mo toxicity
• ECOG PS 0-1 Placebo + nab-paclitaxelc
• Eligible for taxane monotherapy
• Tumour tissue for PD-L1 testing
(N = 902)

Stratification factors
Co-primary endpoints:
• Liver metastases (yes vs no)
• PFSd and OS (hierarchically tested in ITT and
• Prior taxanes (yes vs no)
PD-L1 IC+ populations)
• PD-L1 status (positive vs negative)a

a PD-L1 IC ≥ 1% vs < 1% per VENTANA SP142 assay. b 840 mg IV on days 1 and 15 (28-day cycle). Schmid et al NEJM 2018
c 100 mg/m2 IV on days 1, 8 and 15 (28-day cycle). d Per RECIST 1.1. Emens LA. ESMO 2020
13
OS in the PD-L1 IC+ population
PD-L1 IC+ population
A + nP (n = 185) P + nP (n = 184)
Atezolizumab
OS events, n (%) 120 (65) 139 (76)
Placebo
Stratified HR
0.67 (0.53, 0.86)a
Overall survival

(95% CI)

3-year OS: 36%

Median OS (95% CI):

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

Time (months)

Emens LA. Annals of Oncology 2021 Emens LA. IMpassion130

ESMO 2020
14
 Miles et al. Annals of Oncology 2021
Miles D et al. ESMO 2020
 San Antonio Breast Cancer Symposium®, December 2021

Impassion 130 and 131 (conflicting IO results?)

Impassion 13: FINAL OS in PD-L1 IC+ Population Impassion 131: solvent based paclitaxel + Atezolizumab

225 mo

28 mo

Nab-pac + IO Pac alone

Control arm 131 with paclitaxel alone -mOS = 28 months

is considerably longer than….

Experimental arm 130 with nab-pac + Atezo = 25 months AND

Experimental arm 355 with solvent based pac + Pembro (21 months)
(Heterogeneity of TNBC, unknown confounders…)
 Discussion points for differences in results of IMpassion130 vs.
IMpassion131

◆ TNBC Heterogeneity
◆ Unknown Confounders (eg. antibiotic use/microbiome)
◆ Role of corticosteroids
◆ Differences in efficacy nab- vs solvent paclitaxel dosing
◆ Chance
◆ PD-1 vs. PD-L1 inhibition?

17
KEYNOTE-355 Study Design (NCT02819518)

Key Eligibility Criteria

• Age ≥18 years
• Central determination of TNBC and
PD-L1 expression
Pembrolizumab a + Chemotherapyb
• Previously untreated locally
recurrent inoperable or metastatic
R Progressive
TNBC
• Completion of treatment with 2:1 disease d/cessation
curative intent ≥6 months prior to of study therapy
first disease recurrence
• ECOG performance status 0 or 1
Placebo c + Chemotherapyb
• Life expectancy ≥12 weeks from
randomization
• Adequate organ function
• No systemic steroids Stratification Factors:
• No active CNS metastases • Chemotherapy on study (taxane vs gemcitabine/carboplatin)
• No active autoimmune disease
• PD-L1 tumor expression (CPS ≥1 vs CPS <1)
• Prior treatment with same class chemotherapy in the
neoadjuvant or adjuvant setting (yes vs no)

Cortes J et al. The Lancet 2020

 Baseline Characteristics, ITT
All Subjects, N = 847
Pembro + Chemo Placebo + Chemo
Characteristic, n (%)
N = 566 N = 281
Age, median (range), yrs 53 (25-85) 53 (22-77)
ECOG PS 1 232 (41.0) 108 (38.4)
PD-L1–positive CPS ≥1 425 (75.1) 211 (75.1)
PD-L1–positive CPS ≥10 220 (38.9) 103 (36.7)
Chemotherapy on study
Taxane (Nab-paclitaxel or paclitaxel) 255 (45.1) 127 (45.2)
Gemcitabine/Carboplatin 311 (54.9) 154 (54.8)
Prior same-class chemotherapy
Yes 124 (21.9) 62 (22.1)
No 442 (78.1) 219 (77.9)
Disease-free interval
de novo metastasis 167 (29.5) 84 (29.9)
<12 months 126 (22.3) 50 (17.8)
≥12 months 270 (47.7) 147 (52.3)
Cortes J et al. The Lancet 2020
Cortes J et al. the LANCET 2020
 Progression-Free Survival in Subgroups by
On-Study Chemotherapy

PD-L1 CPS ≥10 Hazard Ratio PD-L1 CPS ≥1 Hazard Ratio ITT Hazard Ratio
for for for
Median PFS (mo) Progression Median PFS (mo) Progression Median PFS (mo) Progression
Pembro Placebo or Death Pembro Placebo or Death Pembro- Placebo or Death
Subgroup N + Chemo + Chemo (95% CI) Subgroup N + Chemo + Chemo (95% CI) Subgroup N + Chemo + Chemo (95% CI)
0.65 0.74 0.82
Overall 323 9.7 5.6 Overall 636 7.6 5.6 Overall 847 7.5 5.6
(0.49 to 0.86) (0.61 to 0.90) (0.69 to 0.97)

On-study chemotherapy On-study chemotherapy On-study chemotherapy

0.57 0.66 0.69

Nab-Paclitaxel 99 9.9 5.5 Nab-Paclitaxel 204 6.3 5.3 Nab-Paclitaxel 268 7.5 5.4
(0.34 to 0.95) (0.47 to 0.92) (0.51 to 0.93)
0.33 0.46 0.57
Paclitaxel 44 9.6 3.6 Paclitaxel 84 9.4 3.8 Paclitaxel 114 8.0 3.8
(0.14 to 0.76) (0.26 to 0.82) (0.35 to 0.93)
Gemcitabine- 0.77 Gemcitabine- 0.86 Gemcitabine- 0.93
180 8.0 7.2 348 7.5 7.5 465 7.4 7.4
Carboplatin (0.53 to 1.11) Carboplatin (0.66 to 1.11) Carboplatin (0.74 to 1.16)

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5
Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI)
Favors Favors Favors Favors Favors Favors
Pembro + Chemo Placebo + Chemo Pembro + Chemo Placebo + Chemo Pembro + Chemo Placebo + Chemo

Rugo H SABCS 2020

21
 ESMO 2021
Overall Survival: PD-L1 CPS ≥10
100 HR P-value
n/N Events
(95% CI) (one-sided)
90 Pembro + Chemo 155/220 70.5% 0.73 0.0093a
58.3% (0.55-0.95)
44.7% Placebo + Chemo 84/103 81.6%
80
Percentage of Patients

48.2%
70
34.0%
60
23.0 months
50
16.1 months
40
30
20
10
0 Rugo H ESMO
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 2021
No. at risk Time, months
220 214 193 171 154 139 127 116 105 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
aPrespecified P value boundary of 0.0113 met.
Hazard ratio (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by the randomization stratification factors. Data cutoff: June 15, 2021.
 Overall Survival in Additional PD-L1 CPS Subgroups
Median OS (mo)
Patients Pembro + Patients Placebo Hazard Ratio
Subgroup n Chemo n + Chemo (95% CI)

Overall 566 17.2 281 15.5 0.89 (0.76 to 1.05)

PD-L1 CPS <1 141 16.2 70 14.7 0.97 (0.72 to 1.32)

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

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

PD-L1 CPS ≥20 140 24.0 64 15.6 0.72 (0.51 to 1.01)

0.0 0.5 1.0 1.5

Hazard Ratio (95% CI)
Favors Favors
Pembro + Chemo Placebo + Chemo

Analysis (HR and 95% CI) in the overall population is based on the stratified Cox regression model; analysis in the subgroups is based on the unstratified Cox model. OS in the CPS 1-9
and CPS 10-19 populations were post-hoc exploratory analyses; OS in the CPS <1 and CPS ≥20 populations were prespecified exploratory analyses. Data cutoff: June 15, 2021.
 San Antonio Breast Cancer Symposium®, December 7-10, 2021

Overall Survival in Additional PD-L1 CPS Subgroups HR HR

100 46.1% 100 37.8%
PD-L1 90 42.9%
n/N Events (95% CI) PD-L1 38.3%
n/N Events (95% CI)
90
CPS <1 80 Pembro + Chemo 124/141 87.9% 0.97 CPS 1-9 80 Pembro + Chemo 181/205 88.3% 1.09
70
(0.72-1.32) (0.85-1.40)
Placebo + 70 Placebo + Chemo 93/108 86.1%
60 61/70 87.1%
OS, %s Chemo 60
16.2 months 13.9 months

OS, %
50 50
14.7 months 15.5 months
40 40
30 30
20 20
10 10
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Time, months Time, months
No. at risk No. at risk
141 133 121 107 92 73 65 51 41 37 33 29 25 14 9 4 1 1 0 205 192 172 137 11797 77 59 54 46 36 30 26 21 17 7 4 1 0
70 67 59 46 41 34 30 26 23 19 15 14 11 8 4 3 2 1 0 108 102 96 86 67 55 41 32 27 24 22 18 17 13 9 7 4 0 0

HR HR
100 55.0% 100 60.2%
PD-L1 n/N Events (95% CI) PD-L1 n/N Events (95% CI)
90 48.7% 90 42.2%
CPS 10-19 80 Pembro + Chemo 56/80 70.0% 0.71 CPS ≥20 80 Pembro + Chemo 99/140 70.7% 0.72
(0.46-1.09) (0.51-1.01)
70 Placebo + 70
33/39 84.6% Placebo + Chemo 51/64 79.7%
60 Chemo 60
20.3 months 24.0 months
OS, %

OS, %
50 17.6 months 50 15.6 months
40 40
30 30
20 20
10 10
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Time, months Time, months
No. at risk No. at risk
80 78 73 62 55 50 44 39 36 32 30 27 25 23 17 12 7 0 0 14013612010999 89 83 77 69 59 54 51 48 36 26 19 10 2 0
39 37 36 32 25 22 19 15 14 12 8 7 7 4 3 3 1 1 0 64 61 55 45 41 33 27 24 21 18 17 15 15 13 9 5 3 1 0
Data cutoff: June 15, 2021.
This presentation is the intellectual property of Javier Cortes. Contact him at jacortes@vhio.net for permission to reprint and/or distribute.
 Poliosis!

Safety of IO in Metastatic TNBC

Organ-specific Immune-related Adverse Events in mTNBC trials
(n>1000 patients)

irAE All grades (%) Grade 3-4 (%) Grade 5 (%)

irAE incidence in mTNBC (any grade)
Dermatologic Pruritis, Rash 18 0.5 0
Hypothyroidism 12 0 0 • Single agent: 18.5%
Endocrine
Hyperthyroidism 5 0.1 0 • Higher in combination trials:
Hepatitis; elevated - 57% atezolizumab+nab-pac
Gastro- transaminases
10 3 0.2
- 42% nab-pac monotherapy
intestinal
Colitis, diarrhea 2.5 0.45 0
Prespecified autoimmune Management guidelines ASCO/NCCN
anemia, lymphopenia, Brahmer et al, J Clin Oncol 2018
Hematologic thrombocytopenia and clotting 4 1 0.2
abnormalities
(SITC) clinical practice guideline on
Respiratory Pneumonitis 3 0.5 0.1
immunotherapy for the treatment of
Adrenal insufficiency, type 1 breast cancer
diabetes, ocular, myositis,
Other (<1%) <1 <0.5 0 Emens et al, J Immuno Cancer 2021
neurological/myositis,
nephritis/elevated creatinine

Early recognition and prompt management essential to optimize outcomes

25 D’Abreo and Adams. Nat Rev Clin Oncol 2019
 Summary of Immune Checkpoint Inhibition
in mTNBC

◆ Two randomized phase III trials confirm benefit, Atezolizumab and

Pembrolizumab
◆ Important to use companion diagnostic relevant to therapeutic agent
(i.e. SP-142 – Atezolizumab; 22C3 CPS score > 10 Pembrolizumab)
◆ Cut offs and thresholds still a work in progress
◆ Likely better biomarker of benefit than PD-L1 – research in progress

◆ Best chemotherapy back bone

◆ If using Atezolizumab, data is only with nab-paclitaxel
◆ If using Pembrolizumab, data suggest can use either taxane or carbo/gem

If on Atezo, continue

Atezo approved in Europe and

other countries

26
 IMpassion 132 Ongoing

Chemotherapy +/- Atezolizumab for Early

Progressing Locally Advanced/Metastatic
TNBC

NCT03371017

27
 OLYMPIA-D & EMBRACA
Phase III PARP Inhibitor Trials (gBRCA)

2:1
Olaparib 300 mg PO BID
Pts with HER2-negative MBC with deleterious or
suspected deleterious gBRCA mutation; previous
(n = 205)
anthracycline and taxane, ≤ 2 previous lines of CT* for
metastatic disease; if HR+, not suitable for ET or
OLYMPIAD progressed on ≥ 1 ET, no PD from prior platinum ≥12 m
since (neo)adj
(N = 302) CT† on 28-d cycles
(n = 97)

2:1
Talazoparib 1 mg PO OD
(n = 287)
Pts with HER2-negative LABC or MBC with deleterious or
suspected deleterious gBRCA mutation; previous
EMBRACA anthracycline and taxane, ≤ 3 previous lines of CT* for
metastatic disease
stratified by previous lines of CT* 0 or >1 if Hx CNS met or
not CT on 21/28-d cycles
(n = 144)

CT = Chemotherapy of physician’s choice (Gemcitabine or Vinorelbine or Eribulin or Capecitabine) **no gemcitabine in OlympiAD**

CONFIDENTIAL
PARPi PFS results

Robson et al. NEJM 2017

Olaparib Chemotherapy Litton. NEJM. 2018;379:753

300 mg bd TPC
Events (%) 163 (79.5) 71 (73.2)

Median PFS, months 7.0 4.2

HR 0.58 95% CI 0.43 to 0.80; P=0.0009

 Sacituzumab Govitecan (SG): First-in-Class
Trop-2‒Directed ADC

• Trop-2 is expressed in all subtypes of breast cancer Linker for SN-38

• Hydrolyzable linker for Humanized
and linked to poor prognosis1,2 anti‒Trop-2
payload release
• Distinct from other ADCs3-6 • High drug-to-antibody antibody
ratio (7.6:1)6 • Directed toward
- Antibody highly specific for Trop-2 Trop-2, an
- High drug-to-antibody ratio (7.6:1) epithelial antigen
expressed on
- Internalization and enzymatic cleavage by tumor many solid
cell not required for the liberation of cancers
SN-38 from the antibody
- Hydrolysis of the linker also releases the
SN-38 cytotoxic extracellularly in the tumor SN-38 payload
microenvironment, providing a bystander effect • SN-38 more
• Accelerated FDA approval for metastatic TNBC in potent than
parent
2020 and fast-track designation in metastatic compound,
urothelial cancer7 irinotecan

ADC, antibody−drug conjugate; TNBC, triple-negative breast cancer; Trop-2, trophoblast cell surface antigen 2.
1. Vidula N et al. J Clin Oncol. 2017;35:15(suppl):Abstract 1075. 2. Ambrogi et al. PLoS One. 2014;9(5):e96993. 3. Goldenberg DM et al. Expert Opin Biol Ther. 2020 Aug;20(8):871-885. 4. Nagayama A et
al. Ther Adv Med Oncol. 2020;12:1758835920915980. 5. Cardillo TM et al. Bioconjugate Chem. 2015;26:919-931. 6. Goldenberg DM et al. Oncotarget. 2015;6:22496-224512. 7. Press Release.
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sacituzumab-govitecan-hziy-metastatic-triple-negative-breast-cancer. Accessed August 26, 2020.
ASCENT: A Phase 3 Confirmatory Study of
Sacituzumab Govitecan in R/R mTNBC

Metastatic TNBC Sacituzumab Govitecan (SG) Endpoints

(per ASCO/CAP) 10 mg/kg IV
days 1 & 8, every 21-day cycle Primary
≥2 chemotherapies for Continue • PFS†
(n=267)
advanced disease R treatment until
Secondary
1: progression or
[no upper limit; 1 of the required unacceptable • PFS for the full
1 Treatment of Physician’s Choice
prior regimens could be toxicity population‡
progression occurred within a (TPC)* • OS, ORR,
12-month period after (eribulin/vino/gem or cape) DOR, TTR,
completion of (neo)adjuvant (n=262) safety
therapy)]
Stratification factors
N=529
• Number of prior chemotherapies (2-3 vs >3) Data cutoff: March 11, 2020
NCT02574455 • Geographic region (North America vs Europe)
• Presence/absence of known brain metastases (yes/no)

ASCENT was halted early due to compelling evidence of 31

efficacy per unanimous DSMC recommendation.

Bardia A et al. NEJM 2021

 Demographics and Patient Characteristics
SG (n=235) TPC (n=233) SG (n=235) TPC (n=233)
Female—no. (%) 233 (99) 233 (100) Previous anticancer regimens†
4 (2-17) 4 (2-14)
—median no. (range)
Median age—yr (range) 54 (29-82) 53 (27-81)
Race or ethnic group—no. (%) Most common previous chemotherapy—no. (%)
White 188 (80) 181 (78) Taxane‡ 235 (100) 233 (100)
Black 28 (12) 28 (12)
Anthracycline§ 191 (81) 193 (83)
Asian 9 (4) 9 (4)
Cyclophosphamide 192 (82) 192 (82)
Other or not specified 10 (4) 15 (6)
ECOG PS—no. (%) Carboplatin 147 (63) 160 (69)
0 108 (46) 98 (42)
Capecitabine 147 (63) 159 (68)
1 127 (54) 135 (58)
Previous PARP inhibitor—no. (%) 17 (7) 18 (8)
BRCA 1/2 mutational status—no. (%)
Positive 16 (7) 18 (8) Previous use of checkpoint inhibitors—no. (%) 67 (29) 60 (26)
Negative 133 (57) 125 (54)
Most common sites of diseaseΙΙ—no. (%)
Unknown 86 (37) 90 (39)
TNBC at initial diagnosis* Lung only 108 (46) 97 (42)

Yes 165 (70) 157 (67) Liver 98 (42) 101 (43)

No 70 (30) 76 (33) Bone 48 (20) 55 (24)
Brain metastases-negative population.
*Patients on study either had TNBC at initial diagnosis or had hormone receptor-positive disease that converted to hormone-negative at time of study entry. †Anticancer regimens refer to any treatment regimen that was
used to treat breast cancer in any setting ‡Includes: Paclitaxel, paclitaxel albumin, and docetaxel. §Includes: Doxorubicin, daunorubicin, epirubicin, and variations of those treatment names. ΙΙBased on independent central
review of target and non-target lesions.
BRCA, breast cancer gene; ECOG PS, Eastern Cooperative Oncology Group performance status; PARP, poly-ADP ribose polymerase; SG, sacituzumab govitecan; TNBC, triple-negative breast cancer; TPC, treatment of
physician’s choice.
Progression-Free Survival (BICR Analysis)

BICR Analysis SG (n=235) TPC (n=233)

No. of events 166 150
Median PFS—mo (95% CI) 5.6 (4.3-6.3) 1.7 (1.5-2.6)
HR (95% CI), P-value 0.41 (0.32-0.52), P<0.0001

Primary endpoint (PFS) assessed by independent central review in the brain metastases-negative population, as pre-defined in the study protocol.
Secondary endpoint (PFS) assessed in the full population (brain metastases-positive and -negative) and PFS benefit was consistent (HR=0.43 [0.35-0.54], P<0.0001).
BICR, blind independent central review; PFS, progression-free survival; SG, sacituzumab govitecan; TPC, treatment of physician’s choice.
 Overall Survival
SG (n=235) TPC (n=233)
No. of events 155 185
Median OS—mo (95% CI) 12.1 (10.7-14.0) 6.7 (5.8-7.7)
HR (95% CI), P-value 0.48 (0.38-0.59), P<0.0001

Assessed by independent central review in the brain metastases-negative population.

OS, overall survival; SG, sacituzumab govitecan; TPC, treatment of physician’s choice.
ASCENT: Assessment of SG vs TPC, by Agent

PFS in ASCENT OS in ASCENT

Gemcitabine (n=29) 2,7 Gemcitabine (n=29) 8,4
Capecitabine (n=31) 1,6 Capecitabine (n=31) 5,2
Vinorelbine (n=47) 1,6 Vinorelbine (n=47) 5,9
Eribulin (n=126) 2,1 Eribulin (n=126) 6,9
SG (n=235) 5,6 SG (n=235) 12,1
0 1 2 3 4 5 6
0 2 4 6 8 10 12 14
Median PFS, months
Median OS, months

Sacituzumab Govitecan TPC (n=233)

(n=235) Eribulin (n=126) Vinorelbine (n=47) Gemcitabine (n=29) Capecitabine (n=31)
ORR 35% 5% 4% 3% 6%
CBR 45% 8% 6% 14% 10%

The efficacy benefit observed with SG was retained when evaluating each TPC chemotherapy agent individually

CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival;
SG, sacituzumab govitecan; TPC, treatment of physician’s choice.
O’Shaughnessy J, et al. ASCO 2021 (Poster 1077)
 TRAEs (All Grade, >20%; Grade 3/4, >5% of Patients)

SG (n=258) TPC (n=224)

TRAE* All grade % Grade 3, % Grade 4, % All grade, % Grade 3, % Grade 4, %
Neutropenia† 63 46 17 43 27 13
Anemia‡ 34 8 0 24 5 0
Haematologic
Leukopenia§ 16 10 1 11 5 1
Febrile neutropenia 6 5 1 2 2 <1
Diarrhoea 59 10 0 12 <1 0
Gastrointestinal Nausea 57 2 <1 26 <1 0
Vomiting 29 1 <1 10 <1 0
Fatigue 45 3 0 30 5 0
Other
Alopecia 46 0 0 16 0 0

• Key grade ≥3 TRAEs (SG vs TPC): neutropenia (51% vs 33%), diarrhoea (10% vs <1%),
leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%)
– G-CSF usage was 49% in the SG arm vs 23% in the TPC arm
– Dose reductions due to TRAEs were similar (22% SG vs 26% TPC)
• No severe cardiovascular toxicity, no grade >2 neuropathy or grade >3 interstitial
lung disease with SG
• No treatment-related deaths with SG; 1 treatment-related death
(neutropenic sepsis) with TPC
• AEs leading to treatment discontinuation were low for SG and TPC:
4.7% and 5.4%
• Patients received a median of 7 treatment cycles of SG, with a median
treatment duration of 4.4 months (range, 0.03-22.9)z

*Patients may report more than 1 event per preferred term. AEs were classified according to the MedDRA systems of preferred terms and system organ class and according to severity by NCI CTCAE
v4.03. †Combined preferred terms of ‘neutropenia’ and ‘decreased neutrophil count’. ‡Combined preferred terms of ‘anemia’ and ‘decreased hemoglobin’. §Combined preferred terms of ‘leukopenia’
and ‘decreased white blood cell count’.
G-CSF, granulocyte-colony stimulating factor; SG, sacituzumab govitecan; TPC, treatment of physician’s choice; TRAE, treatment-related AE.
36
1. Bardia A, et al. N Engl J Med. 2021;384(16):1529-1541. Bardia A, et al. ESMO 2020. Oral LBA17.
Krop I et al. SABCS 2021
Targeting TNBC Vulnerabilities

Bianchini G
Nat Rev Clin Oncology 2021
 Treatment Algorithm Metastatic Triple Negative Breast Cancer
Positive Negative
BIOMARKER TESTING
IHC: PD-L1
Clinical Trial and
IHC:
Biomarker

PD-L1+ (SP142 and/or 22C3 assays) PD-L1– UNMET NEED Molecular Profiling

Molecular: gBRCA+ gBRCA+

PD-L1 +: nab-paclitaxel + atezolizumab gBRCA+: PARP inhibitor or platinum chemotherapy

or taxane, gem/carbo + pembrolizumab c
gBRCA-: Standard chemotherapy*
1L

(pending OS results
gBRCA+: PARP inhibitor or platinum chemotherapy (chemotherapy+ bevacizumab approved in some countries)

(no data on best approach if PD-L1 + and gBRCA + but IO not

approved beyond 1st line)

gBRCA+ : PARP inhibitor or platinum chemotherapy (if not gBRCA+ : PARP inhibitor or platinum chemotherapy (if not
given in 1L)
2L

given in 1L)

gBRCA-: Standard chemotherapy* gBRCA-: Standard chemotherapy*

Sacituzumab govitecan (if available)

3L+

*Standard chemotherapy:
taxane/platinum/eribulin/capecitabine/adriamycin/vinorelbine/CMF
(older non-standard: irinotecan/etoposide)
TMB high, MSI- H: pembrolizumab single agent Dent SOLTI 2020
Acknowledgements

Division of Medical Oncology NCCS

Tira Tan
Jack Chan

International Colleagues
Giampaolo Bianchini
Javier Cortes
Giuseppe Curigliano
Shaheenah Dawood
Nadia Harbeck
Sherene Loi
Sibylle Loibl
Paul Mainwaring
Heather McArthur
Hope Rugo
Peter Schmid
Andy Tutt