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Triple negative breast cancer-new developments
1. Systemic Treatment for Early Stage and
Advanced Triple Negative Breast Cancer
Giuseppe Curigliano MD PhD
University of Milano and European Institute of Oncology, IRCCS
Milano, Italy
2. Triple Negative Breast Cancer
• General concepts
• Heterogeneous disease
• Proliferative, generally chemotherapy
responsive
• Rapid development of resistance
• High risk of early recurrence
• Visceral dominant disease, early/frequent brain
metastases
• Short median survival (<2yrs) after diagnosis of
metastases
• Rare subtypes
• Indolent subtypes, generally in older women
(adenoid cystic)
2 3 4 5 6 7 8 9 10
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
0 1
Annual
Hazard
Rate
Yrs After First Surgery
Other (290 of 1421)
Triple negative (61 of 180)
Lin NU, et al. Cancer. 2008;113:2638-2645. Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.
3. Progress!
General
• Neoadjuvant therapy preferred for all but the smallest tumors
• pCR (no invasive disease in breast or node) associated with a
markedly improved outcome
• Allows the potential to individualize therapy to response
Topics
• Neoadjuvant platinum
• PARP inhibitors
• Immunotherapy
• Alternative regimens
• Next steps?
4. Platinum Added to Taxane/Anthracycline
Chemotherapy in Early Stage TNBC
• Increases pCR (smaller benefit in gBRCA+)
– Increase BCS, decreases extent of axillary surgery
• Increases toxicity when added to AC/T or T/AC regimen
• Improved EFS and OS
– Age related effect needs further investigation
• Possible alternative to anthracycline based
chemotherapy
5. censored
Probability
of
EFS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
No
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72
ofpatientsatrisk
P + C + V 316 311 301 290 283 273 266 257 248
Monthssincerandomization
241 235 228 222 213 206 199 195 188 130 28 9 1 1 0
P + C 160 157 154 151 148 143 134 129 121 118 115 112 111 110 102 97 94 91 55 13 5 3 0
P 158 147 147 142 139 132 125 120 115 112 107 102 98 95 91 87 80 74 41 12 7 3 2 1 0
Paclitaxel+
carboplatin+veliparib
Paclitaxel+
carboplatin
Paclitaxel
Eventsn/N 65/316 30/160 47/158
Paclitaxel + carboplatin + veliparib vs paclitaxel
Paclitaxel + carboplatin + veliparib vs paclitaxel + carboplatin
Paclitaxel + carboplatin vs paclitaxel (post hoc analysis)
0.63(0.43–0.92), P=0.02
1.12(0.72–1.72), P=0.62
0.57(0.36–0.91), P=0.02
4-yearEFS,% (95% CI) 78.2 (73.5–83.2) 79.3 (72.9–86.2) 68.5 (61.3–76.6)
Hazardratio(95%CI)a
Loibl S, et al. Lancet Oncol. 2018;19(4):497-509; Geyer et al. Ann Oncol 2022
BrighTNess Trial: Paclitaxel followed by AC
or with Carboplatin or Carboplatin/Veliparib
Drug completion rate MUCH higher than CALGB 40603: different protocol guidelines
N=634
pCR 4.5 year EFS
6. TMC Neoadjuvant Trial in TNBC:
Weekly Paclitaxel x 8 weeks +/- Weekly Carboplatin followed by AC/EC
717 pts accrued over 10 years; Median FU 67.6 mo.
40.3%
54.5%
43.8%
61.9%
71.6%
77.7%
p<0.001
p<0.001
P=0.075
Δ=14.2%
Age ≤ 50 years Age > 50 years
41.5%
61.0%
45.0%
67.6%
70.7%
79.3%
37.5% 38.1%
41.2%
47.4%
73.5% 73.6%
p<0.001
p<0.001
P=0.042
P=1.0
P=1.0
P=0.393
Multivariable (binary logistic) analysis for factors affecting pCR: Rx-Arm X Age interaction significant in a model including Rx-Arm, Age, cT size, cN status, Family History
Δ=19.5%
pCR (ypT0/is ypN0) No-pCR pCR (ypT0/is ypN0) No-pCR
5-year EFS 84.9% 51.8% 5-year EFS 86.8% 52.6%
(95% CI) (80.39 - 89.41%) (45.33 - 58.27%) (95% CI) (79.16 - 94.44%) (43.19 - 62.01%)
HR (95%CI) 0.248 (0.174 - 0.353)
Δ=33.1%
‘p’ <0.001
HR (95%CI) 0.258 (0.135 - 0.493)
Δ=34.2%
‘p’ <0.001
pCR highly prognostic for
EFS regardless of age
58% premenopausal
89% node positive
78% T> 5cm
Gupta et al, SABCS 2022
Prognostic impact of pCR
7. Long Term Efficacy (n=717)
Platinum Control
5-year EFS 70.7%
(95% CI) (65.8 - 75.6%)
64.1%
(59.00 - 69.20%)
HR (95% CI) 0.798 (0.620 - 1.028)
‘P’ 0.081
Δ=6.6%
Event Free Survival
Control 356 308 264 218 169 141 101 70 45 19 12 7 Control 356 330 287 229 179 147 106 74 48 20 12 7
Platinum 361 326 284 239 190 159 112 79 47 17 12 10 Platinum 361 339 303 252 201 168 122 83 51 19 14 12
Platinum Control
5-year OS 74.4%
(95% CI) (69.70 - 79.10%)
66.8%
(61.70 - 71.90%)
HR (95%CI) 0.740 (0.565 - 0.969)
‘p’ 0.029
Δ=7.6%
Overall Survival
Age < or > 50yrs: 12.5% vs no difference Age < or > 50yrs: 11.2% vs no difference
8. Can we Eliminate Anthracyclines?
Gluz et al JNCI 2017; Sharma et al CCR 2016; Sharma et al CCR 2018; Sharma et al, CCR 2021.
ADAPT-TN; N=336
pCR
no pCR
HR (pCR vs. no pCR)=0.30 95% CI 0.14-0.62; p=0.0001
3 Year RFS 90%
3 Year RFS 66%
55% 56% 59%
100
90
80
70
60
50
40
30
20
10
0
pCR
N=133
BRCA wild-type
%
of
patients
with
pathological
response
All
N=27
BRCA mutated
N=183
p = 0.83
Pooled Analysis of 6 Cycles of Neoadjuvant Carboplatin
plus Docetaxel (CbD) in TNBC
Arm A (CbT
pCR
AC) Arm B (CbD)
50%
40%
30%
20%
10%
0%
100%
90%
80%
70%
60%
pCR and RCB
54%
(26/48)
52%
(27/52)
p = 0.84
NeoStop Trial
TCa/AC vs Tca x 6
N=100
9. RCB 0+I: 12/19 = 63%
(36.7–61.6) (32.0–60.6) (35.0–60.1)
(41.0–57.4)
Litton et al. J Clin Oncol. 2020;38(5):388-394.; Litton et al, ASCO 2021, Abstract 505.
Neoadjuvant Talazoparib and NeoTALA in gBRCA
1 mg a day x 6 months
10
2
5
3
RCB-0 RCB-I RCB-II
Number
of
Patients
BRCA1: 8
BRCA 2:
2
Subtype N
BRCA 1 17
BRCA 2 3
TNBC 15
HR+ 5
53%
N=20
TNBC only
N=61
79% BRCA1
77% stage I/II
Trial closed
early for
‘strategic’
reasons
Evaluable population (N=48)
ITT population (N=61)
95% CI†
80% CI†
45.8% 45.8%
49.2% 47.5%
0
20
40
60
80
100 RCB-III
Evaluable population (N=48)
ITT population (N=61)
by ICR by INV
pCR
rate
(%)*
pCR
(32.0–60.6)
(36.4–55.2)
10. Olympia: Updated Endpoints
Median FU 3.5 years, 2nd IA
Tutt et al. N Engl J Med. 2021;384(25):2394-2405;
Tutt et al. ESMO Plenary 2022.
• 72% BRCA1, 82% TNBC, 50% post NACT
• No increase in MDS/AML compared to placebo
• Most toxicity grade 1/2; nausea most common
• Grade 3
• Anemia 9%, fatigue 2%, neutropenia 5%
Neoadjuvant Group
• TNBC: non-pCR
• Hormone receptor–positive:
non-pCR and CPS+EG score ≥ 3
Adjuvant Group
• TNBC: ≥ pT2 or ≥ pN1
• Hormone receptor–positive:
≥ 4 positive lymph nodes
Invasive
disease-free
survival
(%)
Olaparib (134 events)
Placebo (207 events)
No. at risk
Stratified hazard ratio 0.63 (95% CI: 0.50, 0.78)
0 6 12 18 24 30
Time since randomisation (months)
36 42
0
20
40
60
80
100
48
Olaparib 921 825 777 738 694 603 495 382 293 204
Placebo 915 807 765 715 656 571 459 370 293 187
54
88.4
93.4
81.4
89.7 86.1
77.3
82.7
75.4
Difference: 3 Yr. IDFS rate
8.8% (95% Cl: 5.0%, 12.6%)
Difference: 4 Yr. IDFS rate
7.3% (95% Cl: 3.0%, 11.5%)
Overall
survival
(%)
Olaparib (75 deaths, 70 due to breast cancer)
Placebo (109 deaths, 103 due to breast cancer)
96.9
98.0
92.8
95.0 92.8
89.1
No. at risk
0 6 12 18 24 30
Time since randomisation (months)
36 42
0
20
40
60
80
100
89.8
86.4
48
Olaparib 921 862 844 809 773 672 560 437 335 228
Placebo 915 868 843 808 752 647 530 423 333 218
54
Difference: 3 Yr. OS rate Difference: 4 Yr. OS rate
3.8% (95% Cl: 0.9%, 6.6%) 3.4% (95% Cl: -0.1%, 6.8%)
Stratified hazard ratio 0.68 (98.5% CI: 0.47, 0.97); P = 0.009 crossing the significance boundary of 0.015
Distant
disease-free
survival
(%)
No. at risk
Olaparib
Placebo
Olaparib (107 events)
Placebo (172 events)
921
915
828
818
784
777
746
728
698
670
609
582
Stratified hazard ratio 0.61 (95% CI: 0.48, 0.77)
0 6 12 18 24 30
Time since randomisation (months)
501
471
36
391
379
42
0
20
40
60
80
100
302
300
48
209
193
54
90.3
94.4
84.0
90.6 88.0
81.0
86.5
79.1
Difference: 3 Yr. DDFS rate
7.0% (95% Cl: 3.5%, 10.6%)
Difference: 4 Yr. DDFS rate
7.4% (95% Cl: 3.6%, 11.3%)
11. Chemotherapy results in: Pembrolizumab plus standard neoadjuvant
chemotherapy in TNBC
pCR=pathologic complete response as defined as ypT0/Tis ypN0; TNBC=triple-negative breast cancer; PAC=paclitaxel, doxorubicin, cyclophosphamide.
a Economopoulou P, et al. Ann Oncol. 2016;27:1675-1685; b Schmid P, et al. Ann Oncol. 2020;31:569-581; c Nanda R, et al. JAMA Oncol. 2020;6(5):1-9. Epub ahead of print;
d Bailly C, et al. NAR Cancer. March 2020;2(1).
I-SPY2c
(N=29)
Tumor lysis
and antigen
sheddinga
PD-L1 expressiond
70
60
50
40
30
20
10
0
Pembro + wP/AC wP/AC
pCR
rate,
%
KN173b
(N=60)
100
80
60
40
20
0
Before chemo After chemo
70
60
50
40
30
20
10
0
Pembro + T/AC ± Cb
pCR
rate,
%
RATIONALE FOR COMBINING CHECKPOINT
INHIBITION WITH CHEMOTHERAPY
12. Phase III Neoadjuvant Immunotherapy Trials
N=1174
Newly
diagnosed
TNBC
T1c N1-2 or
T2-4 N0-2
C1-4; 12 wks
Carboplatin
+ Paclitaxel
Pembrolizumab 200 mg
Q3W
C 1-9; 27 weeks
Pembrolizumab 200 mg
Q3W
Placebo
Placebo
R
2:1
S
U
R
G
E
R
Y
AC or EC
AC or EC
Carboplatin
+ Paclitaxel
C5-8; 12 wks
KEYNOTE 522
IMpassion 031
N=602
∆ 16.5% (5.9, 27.1)
P = 0.0044a
57.6%
41.1%
95/165
Atezolizumab-Chemo
69/168
Placebo-Chemo
AEs leading to D/C of any drug:
22.6 v 19.8%
AEs requiring corticosteroids:
12.8 v 9.6%
Schmid et al. N Engl J Med. 2020;382(9):810-821;
Mittendorf et al. Lancet 2020;396(10257):1090-1100.
Patient population
• ~51% node positive
• 75% stage II/25% stage III
• ~56% premenopausal
13. Benefit from
Immunotherapy is
Independent of PD-L1
status
PD-L1 is Predictive of
Response to
Chemotherapy
0
10
20
30
40
50
60
70
80
90
100
CPS <1
pCR,
%
(95%
CI)
10/33
30.3%
45.3%
29/64
Δ 18.3 (-3.3 to 36.8)
0
10
20
30
40
50
60
70
80
90
100
CPS ≥1 CPS ≥20
pCR,
%
(95%
CI)
Δ 17.5 (6.2 to 29.1)
40/64
Δ 18.5 (5.0 to 32.7)
103/126
81.7%
Δ 14.2 (5.3 to 23.1)
68.9%
54.9%
230/334 90/164
77.9%
62.5%
59.8%
162/208 55/92
CPS ≥10
) pCR (95% CI), ypT0/is ypN0 (PD-L1–negative)
47.7%
34.4%
∆ 13.3%
(−0.9, 27.5)
42/88
Atezolizumab-
Chemo
32/93
Placebo-
Chemo
68.8%
49.3%
∆ 19.5% (4.2, 34.8)
P = 0.021b
53/77
Atezolizumab-
Chemo
37/75
Placebo-
Chemo
Did not cross significance
boundar y of 0.0184
pCR (95% CI), ypT0/is ypN0 (PD-L1–positive
Pembro + Chemo
Placebo + Chemo
Schmid et al. SABCS 2019, Abstr. GS3-03;
Mittendorf et al. Lancet 2020;396(10257):1090-1100.
14. EFS and DRFS: Statistically Significant at IA4
Schmid et al, ESMO virtual plenary 2021.
aHazard ratio (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by the randomization stratification factors. bPrespecified P-value boundary of 0.00517 reached at this analysis.
cDefined as the time from randomization to the data cutoff date of March 23, 2021.
Events
HR
(95% CI)
Pembro +
Chemo/Pembro
12.8%
0.61a
(0.46-0.82)
Pbo + Chemo/Pbo 20.3%
Me
84.5%
7.7%
76.8%
Events
HR
(95% CI)
P-value
Pembro + Chemo/Pembro 15.7% 0.63a
(0.48-0.82)
0.00031b
Pbo + Chemo/Pbo 23.8%
dian follow-upc: 39.1 mo
EFS DRFS
87.0%
7.5%
80.7%
15. EFS Subgroup Analyses
0.0 0.5 1.0 1.5
Hazard Ratio (95% CI)
123/784 (15.7)
Primary analysis 93/390 (23.8) 0.63 (0.48 to 0.82)
No. of events/no. of patients (%)
EFS Analyses Pembro+Chemo/Pembro Pbo+Chemo/Pbo
Hazard Ratio
(95% CI)
80/408 (19.6) 57/196 (29.1) 0.65 (0.46 to 0.91)
43/376 (11.4) 36/194 (18.6) 0.58 (0.37 to 0.91)
65/590 (11.7) 54/291 (18.6) 0.60 (0.42 to 0.86)
54/194 (27.8) 39/98 (39.8) 0.68 (0.45 to 1.03)
Pre-menopausal 60/438 (13.7) 47/221 (21.3) 0.62 (0.42 to 0.91)
Post-menopausal 63/345 (18.3) 46/169 (27.2) 0.64 (0.44 to 0.93)
2+ by IHC (but FISH-) 32/188 (17.0) 24/104 (23.1) 0.73 (0.43 to 1.24)
0-1+ by IHC 91/595 (15.3) 69/286 (24.1) 0.60 (0.44 to 0.82)
>ULN 29/149 (19.5) 23/80 (28.8) 0.65 (0.37 to 1.12)
≤ULN 93/631 (14.7) 69/309 (22.3) 0.63 (0.46 to 0.86)
Menopausal status
HER2 status
LDH
Nodal status
Positive
Negative
Stage II
Stage III
Overall disease stage
Favors
Pbo+Chemo/
Pbo
Favors
Pembro+Chemo/
Pembro
Primary analysis based on a Cox regression model with treatment as a covariate stratified by the randomization stratification factors; subgroup analyses based on unstratified Cox model.
Data cutoff date: March 23, 2021.;
Schmid et al, SABCS 2021. Abstract GS1-01; Schmid et al. SABCS 2019. Abstract GS3-03; Data cutoff date: April 24, 2019; FDA ODAC presentation 2.8.21
N-: 88.6 vs 82.2%; 6.4%
N+: 80.7 vs 71.5%; 9.2%
III: 71.8 vs 62%; 9.8%
II: 88.6 vs 81.7%; 6.9%
EFS
Improvement in pCR more pronounced
with higher burden of disease at diagnosis.
16. 94.4%
92.5%
56.8%
67.4%
pCRYes
pCRNo
EFS by pCR (ypT0/Tis ypN0)
65.6%
52.7%
8.5%
10.9%
0
10
20
30
40
50
60
70
80
90
100
Percentage
of
Patients
16.2%
21.9%
4.5%
8.5%
RCB 0-I
RCB
I II III
Pembro + Chemo
Placebo + Chemo
RCB II-III
RCB Frame Shift with
Pembrolizumab at IA1
Schmid et al. SABCS 2019. Abstract GS3-03; Data cutoff date: April 24, 2019
18. What is the Patient Cost of Therapy: Toxicity
0
2
4
6
10
8
12
14
16
18
20
Incidence,
%
Pembro +
Chemo/Pembro
(N = 783)
Pbo +
Chemo/Pbo
(N = 389)
Any grade 43.6% 21.9%
Grade 3-5
Led to death
Led to discontinuation of
any drug
14.9%
0.3%a
10.9%
2.1%
0
2.6%
11.6
15.1
5.7 5.7
1.0
5.2
1.8
2.6
0
2.2
1.5
2.0
1.3
1.9
0.3
1.7
0.8
1.4
0.8
Grade
1-2 3-5
Pembro + Chemo/Pembro
Pbo + Chemo/Pbo
Immune-Mediated AEs and Infusion Reactions with Incidence ≥10 Patients
Neoadjuvant + chemo
Adjuvant
0
2
4
6
8
10
12
14
16
18
20
Incidence,
%
Pembro +
Chemo/Pembro
(N = 588)
Pbo +
Chemo/Pbo
(N = 331)
Any grade
Grade 3-5
Led to death
Led to discontinuation
10.2%
2.9%
0.2%a
1.4%
6.0%
0.3%
0
0.3%
2.9
3.6
1.9
1.2
1.9
0
1.2
0.6
0
0.9 0.6 0.5 0.3 0 0.3 0
1-2
Grade
3-5
Pembro + Chemo/Pembro
Pbo + Chemo/Pbo
A total of 4 deaths occurred in the pembro arm compared to one death in the placebo arm.
TRAEs included sepsis, pneumonitis, PE, and autoimmune encephalitis vs septic shock
19. Ongoing Phase III Trials with IO in TNBC
Neoadjuvant/adjuvant Adjuvant
• Atezolizumab
• NSABP B59/GeparDouze (n=1520)
• Pac/carbo AC/EC
• EFS NeoTRIPaPDL1 (n=272)
• EFS Impassion 031 (n=333)
• Pembrolizumab
• NeoPACT (n=100)
• Docetaxel/carbo/pembro x 6
• Atezolizumab
• Impassion 30 (n=2300)
• Pac AC/EC
• Avelumab
• A-Brave (n=335)
• Adjuvant and post NAC high risk:
avelumab alone
• Pembrolizumab
• SWOG S1418/NRG BR006 (n=1155)
• Post NAC: Pembro vs Obs x 1 yr
• Completed
• On hold at 2200 enrolled
20. Checkpoint Inhibitors in Early TNBC
Variable I-SPY KEYNOTE-522 IMPASSION 031 NeoTRIP GeparNUEVO
Total patients 69/180 1174 (602) 333 280 174
Type of CPi PD1
Pembro x 4
PD1
Pembro x 1 year
PD-L1
Atezo x 1 year
PD-L1
Atezo x 8
PD-L1
Durva x 8
Stage Stage II/III Stage II/III Stage II/III + N3 disease 35% stage I
Anthracycline pre-op yes yes yes No* yes
Included carboplatin no yes No (nab-pac) Yes (nab-pac)
2 wks on, 1 wk off x 8
no
Improved pCR Yes Yes
51.2 v 64.8%
P=0.00055
Yes
41.1 v 57.6%
P=0.0044
No
(43.5 v 40.5%)
Numeric
improvement
(53 v 44%, p=0.18)
Improved EFS NR:
pCR>nonpCR
Yes NR NR Yes
EFS, DDFS and OS
Nanda et al, JAMA Onc 2020; Schmid et al, NEJM 2020 & NEJM 2022; Mittendorf et al, Lancet 2020; Gianni et al, SABCS 2019;
Loibl et al, Ann Oncol 2019 & Ann Oncol 2022
*Callari et al, PD10-09:, SABCS 2021: role of anthracyclines in the modulation of the immune microenvironment
21. KeyEligibility:
pCR after preop chemo x min 6
cycles with pembrolizumab
R
Pembrolizumabx 27wks
Observation
Stratification Factors:
• Baseline nodal status
• Receipt of anthracycline chemotherapy: yes vs. no
TNBC: Immunotherapy for Early-Stage Disease
Questions (1)
• Optimal duration of CPI if pCR achieved?
• Balancing risk
OptimICE-pCR
• Can we identify a group of patients who will do
well with chemotherapy alone?
• Optimal post-neoadjuvant therapy
• Should we combine or sequence
pembrolizumab with other post-
neoadjuvant therapies?
• Optimal chemotherapy backbone
• Role of platinum salts established
• Alternate chemotherapy regimens?
PI: Tolaney
Alliance Trial
22. Alternative NeoAdjuvant Regimens for TNBC
• NeoPACT:
• Pembrolizumab/docetaxel/carboplatin x 6 cycles
• 109 evaluable, 88% stage 2-3
• Stage II-III, ER & PR IHC <1%
• pCR and RCB 0+1 59% and 69%
• >30% TILS and immune signature predict pCR
• 2-year EFS with pCR: 98%
• NeoSTAR: Sacituzumab govitecan x 4
• N=50 (12 stage I disease, 26 stage II, 11 stage III; 62%
node neg; 9 pts gBRCA+).
• pCR rate 30% (n= 15/50; (18%, 45%); RCB1, 3
• Ongoing study plus pembrolizumab
30%
50%
27%
18%
75%
pCR rates overall, by stage, and by gBRCA status
Rates of pCR
Sharma et al. ASCO 2022. Abstract 513; Spring et al. ASCO 2022. Abstract 512.
100%
80%
60%
40%
20%
0%
ALL
(N=109)
Node
negative
(N=68)
Node
positive
(N=41)
ER and PR
<1%
(N=92)
ER/PR
1-10%
(N=17)
PD-L1
positive
(N=50)
PD-L1
negative
(N=56)
58%
69%
65%
78%
46%
55%
59%
72%
53%
65%
76%
86%
39%
53%
pCR
RCB 0+1
23. More Questions
• Who needs checkpoint inhibitors?
• What is the size threshold for use of pembrolizumab?
• Adjuvant stage II/III: Reasonable to deliver KN522 regimen as adjuvant therapy
• Post-neoadjuvant to follow!
• Biomarkers: not ready for prime time?
• Use of TILS in clinical practice: can we use a specific cutoff to determine who could
forgo chemotherapy in ESBC?
• Prognostic with a cutoff of 30% - stratification of chemotherapy?
• Stage 1 disease, no chemo, TILS>50%, DRFS 87% at 10 years – is that good enough?
• Young women, N0, with >75% TILS? OS at 15 years 93%
• Immune signatures – unless all or none, hard to know how to use this data for upfront
decision making
• ctDNA: change Rx to optimize pCR (ctDNA clearance associated with pCR in I-SPY2)
Loi et al, JCO 2019, Leon-Ferre et al, submitted, de Jong et al, JCO 2022; Magbanua et al, AACR 2022
24. Next Steps in the Neoadjuvant Setting
TNBC:
cT1a-b N1-N2
or
cT1c-T3 N0-N2
N=130
sTIL
Assessmenton
Core Needle Biopsy
MRI 2
Surgery
MRI2
Surgery Adjuvant Therapy3
t Therapy3
US2
MRI & US
Tumor Tissue
Adjuvant Therapy3
High sTILs (≥30%)
Adjuvant Therapy3
Intermediate sTILs (5-29%)
RD
Surgery Adjuvant Therapy3
US2
rPR
SD
Ne
Res
oadjuvant TIL- and
ponse-Adapted
Ineligible:
1Mid-treatment MRI preferred, but can consider delaying to end-of-treatment if it will impact surgical approach; 2Imaing will include axillary US cN+ at diagnosis; 3Adjuvant radiotherapy per standard-of-care, adjuvant systemic therapy per MD discretion
Chemoimmunotherapy
for TNBC (NeoTRACT)
PrimaryObjective
Determine pathologic complete response (pCR) rate in high,
intermediate and low-stromal tumor infiltrating lymphocytes
(sTILs) categories
Secondary Objectives
RCB, radiographic response in TIL categories
Immune biomarkers, ctDNA and other circulating biomarkers
Surgery should occur 4-8 weeks after the last cycle of systemic therapy
Treatment per MD Discretion / Multidisciplinary Consensus
Treatment per MD Discretion / Multidisciplinary Consensus
Any T4, Any N3
Any M1
Carboplatin/Docetaxel + Pembrolizumab
Doxorubicin/Cyclophosphamide + Pembrolizumab Low/Absent sTILs (<5%)
rCR Radiographic complete response US2 ± MRI1 Surgery Adjuvan
rPR Radiographic partial response
rSD Radiographic Stable disease
rPD Progressive disease
MRI1,2
pCR Pathologic complete response
RD Residual disease
Blood collection Treatment per MD Discretion / Multidisciplinary Consensus
Highly Recommended
PI: Shane Stecklein and Priyanka Sharma
University of Kansas MedicalCenter
Wolf, Yau et. al. Cancer Cell 2022
Non-anthracycline regimen Stratify treatment based on TILS
ISPY2.2: Individualize therapy based on biology and on
response in the neoadjuvant setting; test new agents first
25. Todays Roadmap for Early TNBC
T1c, N0
T>2cm, any N+
Neoadjuvant
therapy
Taxane/platinum vs
T/AC
gBRCA mutation: neoadjuvant PARP inhibitors?
TCa/AC + pembrolizumab
Surgery
Olaparib x one year
Capecitabine
pCR
No pCR
No further therapy
Complete one year
pembrolizumab?
gBRCA mut
Wild type
pembrolizumab
T1a/b, N0 Surgery +/- chemotherapy taxane/carboplatin vs docetaxel/cyclophosphamide
AC: anthracycline/cyclophosphamide; Ca: carboplatin
Non-anthracycline
regimens?
26. Rational for the Combination of Chemotherapy
& Immunotherapy
Chemotherapy induces multiple immunomodulatory changes in the tumor
microenvironment that may influence the effectiveness of immunotherapy
M1, tumor-associated macrophage; MHC, major histocompatibility complex; TNF-α, tumor necrosis factor alpha
1. Daly ME, et al. J Thorac Oncol 2015; 2. Kaur P, et al. Front Oncol 2012; 3. Deng L, et al. J Clin Invest 2014
27. 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-L1IC+: PD-L1in ≥ 1% of IC as percentage of tumour area assessed with the VENTANASP142assay.
NCT02425891.Stratification factors: prior taxane use, liver metastases and PD-L1IC status. Co-primary endpoints in ITT and PD-L1IC+: PFS and OS.
Clinical cutoff date: 2January 2019.
Schmid et al, NEJM 2019;Schmid and Rugo et al., Lancet Oncol 2020
Population
Median OS HR
(95% CI)
PD-L1 IC+
A + nP P + nP
25.0 mo 18.0 mo
0.71
(0.54, 0.93)
PD-L1 IC- 19.7 mo 19.6 mo
0.97
(0.78, 1.20)
Population
Median PFS HR
(95% CI)
A + nP P + nP
PD-L1 IC+ (41%) 7.5 mo 5.3 mo
0.63
(0.50, 0.80)
PD-L1 IC- (59%) 5.6 mo 5.6 mo
0.93
(0.77, 1.11)
(IC+, n = 185)
(IC+, n = 184)
(IC-, n = 266)
(IC-, n = 267)
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
A + nP
P + nP
A + nP
P + nP
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
100
90
80
70
60
50
40
30
20
10
100
90
80
70
60
50
40
30
20
10
Overall
Survival
(%)
Progression-Free
Survival
(%)
Months
Months
28. 9
IMpassion 130: OS in the PD-L1 IC+ population
Data cutoff, 14 April 2020. NE, not estimable.
a P value not displayed since OS in the PD-L1+ population was not formally tested due to the hierarchical study design.
PD-L1 IC+ population
A + nP (n = 185) P + nP (n = 184)
OS events, n (%) 120 (65) 139 (76)
Stratified HR
(95% CI)
0.67 (0.53, 0.86)a
Emens et al: Ann Oncol 2021
IMpassion130 Final OS. 2
25.4 mo
(19.6, 30.7)
3-year OS: 36%
Time (months)
Overall
survival
3-year OS: 22%
Median OS (95% CI):
17.9 mo
(13.6, 20.3)
No. at risk
(PD-L1+ population):
A + nP
P + nP
Subset Analysis for OS (HR)
• Prior taxane:
• 0.83 (0.59-1.15)
• No prior taxane:
• 0.55 (0.38-0.80)
30. KEYNOTE 355: Progression-Free Survival
PD-L1 CPS ≥1 PD-L1 CPS ≥10
ITT
Prespecified P value boundary of
0.00411 met
Prespecified P value boundary of
0.00111 not met
Statistical significance was not tested due
to the prespecified hierarchical testing
strategy
75% of pts 38% of pts
Subset analyes suggest greater benefit with taxane partner, de novo disease, >12 month DFI Cortes et al, Lancet 2020
31. Overall Survival: PD-L1 CPS ≥10
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.
n/N Events
HR
(95% CI)
P-value
(one-sided)
Pembro + Chemo
Placebo + Chemo
155/220
84/103
70.5%
81.6%
0.73
(0.55-0.95)
0.0093a
58.3%
44.7%
23.0 months
16.1 months
48.2%
34.0%
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
100
90
80
70
60
50
40
30
20
10
0
Time, months
Percentage
of
Patients
No. at risk
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
Rugo et al, ESMO 2021
32. Overall Survival in Subgroups: CPS ≥10
0 2 3
<65
≥65
0
1
Nab-paclitaxel
Gemcitabine-Carboplatin
Yes
No
Yes
No
16.1
Placebo
+ Chemo
Median OS (mo)
19.8
10.6
18.4
14.9
16.9
17.1
13.0
23.0
Pembro +
Chemo
26.4
17.7
29.8
23.5
22.8
20.3
28.3
0.73 (0.55 to 0.95)
Hazard Ratio
for Death
(95%)
0.70 (0.49 to 1.00)
0.70 (0.47 to 1.05)
0.63 (0.39 to 1.03)
0.60 (0.32 to 1.09)
0.74 (0.55 to 1.00)
0.86 (0.61 to 1.22)
0.53 (0.34 to 0.80)
Overall
Age (years)
ECOG PS
On-study chemotherapy
Prior same-class chemotherapy
Prior (neo)adjuvant chemotherapy
Number of metastatic sites
Subgroup
323
16.8
12.6
21.8
28.3
0.78 (0.58 to 1.05)
0.51 (0.28 to 0.92)
257
66
196
127
99
65
258
193
130
<3 18.8
32.1 0.63 (0.43 to 0.91)
184
≥3 13.2 10.5 0.75 (0.51 to 1.10)
138
N
Geographic region
N America/EU/ANZ
Asia
Rest of world
Disease-free interval
<12 months
≥12 months
de novo metastasis
212
56
55
23.5
26.7
18.0
15.2
17.4
22.0
0.72 (0.52 to 1.00)
0.44 (0.23 to 0.84)
1.07 (0.57 to 1.98)
104
65
153
26.4
17.1
24.9
12.5
19.7
17.1
0.54 (0.34 to 0.86)
1.44 (0.73 to 2.82)
0.65 (0.45 to 0.96)
Paclitaxel 8.5
16.2
28.6
19.1
0.34 (0.16 to 0.72)
0.88 (0.61 to 1.25)
44
180
1
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.
Data cutoff: June 15, 2021.
34. Immune-Mediated AEs
Immune-Mediated AEs with Incidence ≥10 Patients in Either Treatment Groupa
aBased on a list of terms prespecified by the sponsor and included regardless of attribution to study treatment or immune relatedness by the investigator; related terms included.
Data cutoff: June 15, 2021.
0
2
4
10
8
6
12
14
16
20
18
Incidence,
%
Grade
1-2 ≥3
Pembro + Chemo
Placebo + Chemo
All Immune-Mediated
Pembro +
Chemo
(N = 562)
Placebo +
Chemo
(N = 281)
Any grade 26.5% 6.4%
Grade 3-5 5.3% 0.0%
Led to death 0.0% 0.0%
Led to discontinuation 2.8% 0.0%
of any drug
15.8
3.2
4.3
1.1
0
2.5
1.4
1.8 1.8
0.4
35. 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 (%)
Dermatologic Pruritis, Rash 18 0.5 0
Endocrine
Hypothyroidism 12 0 0
Hyperthyroidism 5 0.1 0
Gastro-
intestinal
Hepatitis; elevated
transaminases
10 3 0.2
Colitis, diarrhea 2.5 0.45 0
Hematologic
Prespecified autoimmune
anemia, lymphopenia,
thrombocytopenia and clotting
abnormalities
4 1 0.2
Respiratory Pneumonitis 3 0.5 0.1
Other (<1%)
Adrenal insufficiency, type 1
diabetes, ocular, myositis,
neurological/myositis,
nephritis/elevated creatinine
<1 <0.5 0
D’Abreo and Adams. Nat Rev Clin Oncol 2019
irAE incidence in mTNBC (any grade)
• Single agent: 18.5%
• Higher in combination trials:
- 57% atezolizumab+nab-pac
- 42% nab-pac monotherapy
Management guidelines ASCO/NCCN
Brahmer et al, J Clin Oncol 2018
(SITC) clinical practice guideline on
immunotherapy for the treatment of
breast cancer
Emens et al, J Immuno Cancer 2021
Early recognition and prompt management essential to optimize outcomes
Poliosis!
36. Immunotherapy: First-Line Rx for mTNBC
IMPASSION 131 IMPASSION 130 KEYNOTE 355
N (PD-L1+) 943 (292, 45%)
>1%
902 (369, 41%)
>1%
847 (332, 38%)
CPS>10
Randomization
and Treatment
2:1
Paclitaxel 90 mg/m2
Atezolizumab
1:1
nab-Paclitaxel 100
mg/m2
Atezolizumab
2:1
Pac/nab/gem+carbo
Pembrolizumab
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
P=0.2
5 7.5 mo; HR 0.62
P<0.0001
5.6 9.7 mo; HR 0.65
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
37. Roche Withdraws US Atezolizumab Approval for TNBC
• OS was not formally testable due to the hierarchical pre-specified statistical
analysis plan
• IMPASSION 131 is a negative trial, for unclear reasons
• Accelerated approval requires confirmatory data
• This led to the following press-release:
• Aug 27, 2021 - Roche today announced that the company has made the
decision to voluntarily withdraw the US accelerated approval for
Tecentriq® (atezolizumab) in combination with chemotherapy (Abraxane®,
albumin-bound paclitaxel; nab-paclitaxel) for the treatment of adults with
unresectable locally advanced or metastatic triple-negative breast cancer
(mTNBC) whose tumors express PD-L1
• Approval remains active in other countries where the combination in fully
approved
38. PD-L1 Positive TNBC Subpopulations: SP142 and
22C3
Rugo et al, JCNI 2021
OPA: overall percentage agreement, PPA: positive PA; NPA: negative PA
SP142: % tumor area with PD-L1+
immune cells
Pos: >1% (41% in IMP130)
CPS (combined positive score):
# PD-L1+ tumor and immune cells
divided by #TCs x 100
Pos: CPS >10 (38% in KN355)
Does it make a difference if the
inhibitor blocks PD-L1 or PD-1?
NSABPB59/GeparDouze results will
help (1500 pt neoadjuvant study)
39. What is the Evidence: IO in Advanced TNBC
Combining immune checkpoint inhibitors with chemotherapy
Improved PFS in two randomized phase III trials; OS benefit with
prembrolizumab and unconfirmed OS benefit with atezolizumab
Benefit is limited to the population of patients whose tumors test positive
for PD-L1
U.S. FDA has given full approval for pembrolizumab combined with either
paclitaxel, nab-paclitaxel or gemcitabine/carboplatin in PD-L1+ mTNBC
Only a minority of patients benefit (38% in KN355)
Median OS still too short!
PD-L1
An imperfect biomarker although the best to date
Enrichment in PD-L1 positivity associated with efficacy (CPS >10)
Use the right PD-L1 test for the checkpoint inhibitor
40. New Directions and Selected Ongoing Trials
• IMpassion 132
• Gem/Carbo or capecitabine with atezolizumab or placebo in early relapsers
Esteva FJ, et al. Lancet Oncol. 2019;20(3):e175–e186; Rugo et al, ESMO TIP 2020
41. TONIC Trial
Radiotherapy
3x 8 Gy
Doxorubicin
2x 15 m g IV
Cyclophosphamide
2 weeks 50 m g daily
Cisplatin
2x 40 mg / kg IV
Control
N o induction
Randomization
anti-PD1
2 weeks
anti-PD1
anti-PD1
anti-PD1
anti-PD1
biopsy + blood biopsy + blood biopsy + blood
8 weeks
Voorwerk et al, Nat Medicine 2019
Anti-PD1: Nivolumab
7 patients who died within 6 weeks of nivolumab are not included
42. TBCRC 047:
InCITe Updated Trial Design
PI: Hope S. Rugo; Co-PI: Ingrid Mayer
Metastatic TNBC
• Measurable disease
• No more than 2 prior
metastatic lines of
chemotherapy
• Known PD-L1 status
• Prior IO allowed
Tumor biopsy
Blood collection
Sacituzumab
govitecan
Binimetinib Binimetinib + Avelumab +
Liposomal doxorubicin
Sacituzumab govitecan +
Avelumab
Avelumab +
Liposomal doxorubicin
Tumor biopsy
Blood collection
15 day lead-in
1 Cycle=4 weeks
Tumor assessments & PRO q 8 wks
Blood collection (at
8 weeks and at PD)
*Novel agent 1: Binimetinib, a MEK inhibitor (oral)
#Novel agent 2: Sacituzumab govitecan
Avelumab: PD-L1 inhibitor, IV every 2 wks
Liposomal doxorubicin: IV every 4 wks
R
E
G
I
S
T
E
R
R
A
N
D
O
M
I
Z
E
Liposomal
doxorubicin
*Safety combination data from MiLO trial
#Safety combination data from several ongoing trials
43. A166 HER2 Trastuzumab ND ND Phase 1/2 BC Klus Pharma, Inc.
ALT-P7 (HM2-MMAE) HER2 HM2 MMAE ND Phase 1 mBC Alteogen, Inc.
ARX788 HER2 ND Amberstatin269 1.9 Phase 1 mBC Ambrx Biopharma
DHES0815A
(anti-HER2/PBC-MA) HER2 ND PBD-MA ND Phase 1 mBC Genentech and Roche Holding AG
MEDI4276 HER2 Trastuzumab scFv AZI13599185 4 Phase 1 BC MedImmune, LLC
XMT-1522 (TAK-522) HER2 HT-18 AF-HPA 12 Phase 1 BC Mersana Therapeutics, Inc.
AVID100 EGFR MAB100 DM1 ND Phase 1/2 TNBC Formation Biologics, Inc.
CAB-ROR2-ADC Ror2 CAB ND ND Phase 1/2 TNBC BioAtla
Anti-CA6-DM4 immunoconjugate (SAR566658) CA6 DS6 SPDB-DM4 1 Phase 2 TNBC Sanofi
HER2/3=human epidermal growth factor receptor 2/3; MMAE=monomethyl auristatin E; ND=not defined; PBD-MA=pyrrolo benzodiazepine monoamide; T-
DM1=trastuzumab emtansine; T-DXd=trastuzumab deruxtecan; (m)TNBC=(metastatic) triple-negative breast cancer; TROP-2=trophoblast cell surface antigen
2.
1. Nagayama A, et al. Ther Adv Med Oncol. 2020;121758835920915980; 2. Rinnerthaler G, et al. Int J Mol Sci. 2019;20:1115.
Overview of ADCs in
ADC
de
Target
velopmen
t Antibody
for breas
Payload
t can
DAR
cer
Clinical programme Company
Trastuzumab emtansine (T-DM1, KADCYLA) HER2 Trastuzumab DM1 3.5 Approved in mBC with prior therapy, multiple trials in mBC Roche Holding AG
Trastuzumab deruxtecan (T-DXd, DS-8201, ENHERTU) HER2 Trastuzumab DXd 8 Approved in mBC with two prior therapies, multiple trials in mBC
AstraZeneca and
Daiichi Sankyo
(vic-)trastuzumab duocarmazine (SYD985) HER2 Trastuzumab Seco-DUBA 2.8 Phase 1 BC, Phase 3 mBC Synthon Biopharmaceuticals B
Sacitzumab govitecan (TRODELVY) TROP2 RS7 SN-38 7.6
Approved in TNBC with two prior therapies, multiple trials in
mTNBC, mBC
Gilead Sciences, Inc.
Datopotamab deruxtecan (Dato-DXd, DS-1062) TROP2 Datopotamab DXd 4 Phase 1 TNBC and HR+/HER2- AstraZeneca and Daiichi Sanky
Ladiratuzumab vedotin (SGN-LIV1A) LIV1 hLIV22 Vc-MMAE 4 Phase 1 mBC, Phase 1/2 mTNBC Seagen
RC48-ADC HER2 Hertuzumab MMAE 4 Phase 1 BC RemeGen Co
Patritumab deruxtecan (U3-1402) HER3 Patritumab DXd 8 Phase 1/2 mBC Daiichi Sankyo
We will discus s these ADC s in mo re detail in this session
ADC=antibody-drug conjugate; A F-HPA=auristatin F-hydrox ypropylamide; DM 1=merta nsine; DXd=trastuzumab deruxtecan; mBC=metastatic breast cancer;
44. Sacituzumab Govitecan (SG): First-in-Class
Trop-2‒Directed ADC
• Trop-2 is expressed in all subtypes of breast
cancer and linked to poor prognosis1,2
• Distinct from other ADCs3-6
- Antibody highly specific for Trop-2
- High drug-to-antibody ratio (7.6:1)
- Internalization and enzymatic cleavage by
tumor cell not required for the liberation of
SN-38 from the antibody
- Hydrolysis of the linker also releases the
SN-38 cytotoxic extracellularly in the tumor
microenvironment, providing a bystander effect
• Accelerated FDA approval for metastatic
TNBC in 2020 and fast-track designation in
metastatic urothelial cancer7
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.
Humanized
anti‒Trop-2
antibody
• Directed toward
Trop-2, an
epithelial
antigen
expressed on
many solid
cancers
SN-38 payload
• SN-38 more
potent than
parent
compound,
irinotecan
Linker for SN-38
• Hydrolyzable linker for
payload release
• High drug-to-antibody
ratio (7.6:1)6
45. Sacituzumab Govitecan: Phase I/II Trial in mTNBC
108 patients with refractory mTNBC
Median of 3 prior lines of therapy (range 2-10) in the advanced setting
Confirmed ORR = 33.3% (36/108)
Bardia et al. NEJM. 2019.
Clinical benefit rate (CR+PR+SD≥6 mo) = 45.4% (49/108)
Grade 3/4 toxicity:
Neutropenia: 41%; FN 8%
N/V/D: 5/5/8%
Alopecia: 36%
46. ASCENT: Phase III Confirmatory Trial of SG in
Refractory Metastatic TNBC
• 529 pts with mTNBC and >2 chemotherapies for advanced disease
• Randomized 1:1 to SG (10 mg/kg D1, 8 q 21d) vs TPC (eribulin,
vinorelbine, gemcitabine, capecitabine)
• Primary endpoint: PFS in patients without brain metastases
• Pre-defined maximum 15% cap for pts with brain mets
• Demographics
• TPC: 53% eribulin, 20% vinorelbine, 15% gemcitabine, 13% capecitabine
• 70% TN at initial diagnosis
• Median prior regimens 4 (2-17)
• ~88% with visceral disease
Bardia et al, NEJM 2021
ASCENT halted early due to compelling evidence of efficacy by unanimous DSMC recommendation
48. ASCENT: Assessment of SG vs TPC, by Agent
PFS in ASCENT
5,6
2,1
1,6
1,6
2,7
0 1 5 6
Gemcitabine(n=29)
Capecitabine (n=31)
Vinorelbine (n=47)
Eribulin (n=126)
SG (n=235)
2 3 4
Median PFS, months
OS in ASCENT
12,1
6,9
5,2
5,9
8,4
0 2 4 10 12 14
Gemcitabine (n=29)
Capecitabine (n=31)
Vinorelbine (n=47)
Eribulin (n=126)
SG (n=235)
6 8
Median OS, months
Sacituzumab Govitecan
(n=235)
TPC (n=233)
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. ASCO2021(Poster 1077).
49. Overall Response and Best Percent Change
From Baseline in Tumour Size
SG
(n=235)
TPC
(n=233)
ORR—no. (%) 82 (35) 11 (5)
P-value <0.0001
CR 10 (4) 2 (1)
PR 72 (31) 9 (4)
CBR—no. (%) 105 (45) 20 (9)
P-value <0.0001
Median DOR
—mo (95%CI)
6.3 (5.5−9.0)
3.6
(2.8−NE)
P-value 0.057
SG
TPC
Bardia et al, NEJM 2021
50. Comparable
Benefit Across
Age Groups
Kalinsky et al, ASCO 2021
≥65 y
PFS BICR Analysis SG (n=44) TPC (n=46)
No. of events 30 33
Median PFS—mo (95% CI) 7.1 (5.8-8.9) 2.4 (1.4-2.9)
HR (95% CI), P value 0.22 (0.12-0.40), P<0.0001
<65 y
PFS BICR Analysis SG (n=191) TPC (n=187)
No. of events 136 117
Median PFS—mo (95% CI) 4.6 (3.7-5.7) 1.7 (1.5-2.5)
HR (95% CI), P value 0.46 (0.35-0.59), P<0.0001
≥65 y
SG (n=44) TPC (n=46)
No. of events 22 35
Median OS—mo (95% CI) 15.3 (12.4-NE) 8.2 (5.6-9.8)
HR (95% CI), P value 0.37 (0.22-0.64), P=0.0003
<65 y
SG (n=191) TPC (n=187)
No. of events 133 150
Median OS—mo (95% CI) 11.2 (9.9-13.4) 6.6 (5.3-7.4)
HR (95% CI), P value 0.50 (0.40-0.64), P<0.0001
51. ASCENT: Exploratory analysis of TROP2 and gBRCA
• Trop-2 expression assessed by IHC
• H-score <100 (including H-score 0): Trop-2 Low
• H-score 100-200: Trop-2 Medium
• H-score 200-300: Trop-2 High
• Clinical benefit with SG versus TPC in previously treated
mTNBC is irrespective of level of Trop-2 expression
SG (n=235) TPC (n=233)
Trop-2 High | H-score: 200-300 Trop-2 Medium | H-score: 100-
200
Trop-2 Low | H-score: <100
SG (n=85) TPC (n=72) SG (n=39) TPC (n=35) SG (n=27) TPC (n=32)
Median PFS—mo (95% CI) 6.9 (5.8-7.4) 2.5 (1.5-2.9) 5.6 (2.9-8.2) 2.2 (1.4-4.3) 2.7 (1.4-5.8) 1.6 (1.4-2.7)
Median OS—mo (95% CI)
Trop-2 High | H-score: 200-300
SG (n=85) TPC (n=72)
14.2 (11.3-17.5) 6.9 (5.3-8.9)
Trop-2 Low | H-score: <100
SG (n=27) TPC (n=32)
9.3 (7.5-17.8) 7.6 (5.0-9.6)
Trop-2 High
H-score: 200-300
(n=157)
Trop-2 Medium
H-score: 100-200
(n=74)
Trop-2 Medium | H-score: 100-
200
SG (n=39) TPC (n=35)
14.9 (6.9-NE) 6.9 (4.6-10.1)
Trop-2 Low
H-score: <100
(n=59)
SG (n=85) TPC (n=72) SG (n=39) TPC (n=35) SG (n=27) TPC (n=32)
ORR—% (no.) 44% (37) 1% (1) 38% (15) 11% (4) 22% (6) 6% (2)
95% CI 33-55 0-8 23-55 3-27 9-42 1-21 Hurvitz et al, SABCS 2020
52. TRAEs (All Grade, >20%; Grade 3/4, >5% of
Patients)
53
SG (n=258) TPC (n=224)
TRAE* All grade % Grade 3, % Grade 4, % All grade, % Grade 3, % Grade 4, %
Haematologic
Neutropenia† 63 46 17 43 27 13
Anemia‡ 34 8 0 24 5 0
Leukopenia§ 16 10 1 11 5 1
Febrile neutropenia 6 5 1 2 2 <1
Gastrointestinal
Diarrhoea 59 10 0 12 <1 0
Nausea 57 2 <1 26 <1 0
Vomiting 29 1 <1 10 <1 0
Other
Fatigue 45 3 0 30 5 0
Alopecia 46 0 0 16 0 0
• 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
• 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
*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.
1. Bardia A, et al. N Engl J Med. 2021;384(16):1529-1541.
Bardia A, et al. ESMO 2020. Oral LBA17.
53. ASCENT: Exploratory Safety Analyses
By UGT1A1 Allele Status
54
Conclusions: Individuals with UGT1A1 *28/*28 genotype were at modestly higher risk for anemia and febrile neutropenia with
SG and should be monitored closely. These data suggest that UGT1A1 status does not alter recommendations for treatment or
management. Note: The frequency of *28/*28 mutation was low, so this limited the ability to discern additional differences.
UGT1A1 *28/*28 had
higher rates of:
Grade ≥3 treatment-related AESIs (*28/*28 vs *1/*1 vs *1/*28)
• Anemia: 15% vs 4% vs 6%
• Febrile neutropenia: 18% vs 3% vs 6%
• Diarrhoea: 15% vs 10% vs 9%
Treatment Discontinuations
(*28/*28 vs *1/*1 vs *1/*28)
• 6% vs 2% vs 1%
SG (n=250)a
*1/*1 Wild-Type (n=113) *1/*28 Heterozygous (n=96) *28/*28 Homozygous (n=34)
TRAEb All Grade, % Grade ≥3, % All Grade, % Grade ≥3, % All Grade, % Grade ≥3, %
Neutropeniac 76 (67) 60 (53) 55 (57) 45 (47) 24 (71) 20 (59)
Anemiad 37 (33) 5 (4) 29 (30) 6 (6) 16 (47) 5 (15)
Haematologic
Leukopeniae 18 (16) 10 (9) 13 (14) 9 (9) 8 (24) 5 (15)
Lymphopeniaf 10 (9) 1 (1) 5 (5) 1 (1) 4 (12) 2 (6)
Febrile neutropenia 3 (3) 3 (3) 5 (5) 5 (5) 6 (18) 6 (18)
Thrombocytopeniaf 3 (3) 0 6 (6) 0 4 (12) 4 (12)
Gastrointestinal Diarrhoea 65 (58) 11 (10) 57 (59) 9 (9) 21 (62) 5 (15)
Assessed in the safety population of patients with UGT1A1 genotype. Shown are key TRAEs significantly impacted by the UGT1A1 *28/*28 genotype. Other TRAEs like nausea, vomiting,
constipation, fatigue, alopecia, and decrease appetite were not significantly impacted. aSeven patients had UGT1A1 genotypes not listed in the table. bPatients may report more than 1 event per
preferred term. Adverse events were classified according to the MedDRA systems of preferred terms and system organ class and according to severity by NCI CTCAE v4.03. cCombined preferred
terms of “Neutropenia” and “Decreased neutrophil count.” dCombined preferred terms of “Anemia” and “Decreased hemoglobin.” eCombined preferred terms of “Leukopenia” and “Decreased white
blood cell count.” fCombined preferred terms of “Lymphopenia” and “Decreased lymphocyte count.” fCombined preferred terms of “Thrombocytopenia” and “Decreased platelet count.”
SG, sacituzumab govitecan; TRAE, treatment-related adverse event; UGT1A1, UDP glucuronosyltransferase family 1 member A1.
1.Rugo H, et al. Poster. SABCS [virtual meeting]. 2020 (abstr PS11-09).
54. Sacituzumab in ER+ MBC
n=54
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
B
e
s
t
R
e
s
p
o
n
s
e
(%
c
h
a
n
g
e
in
ta
r
g
e
t
le
s
io
n
f
r
o
m
b
a
s
e
lin
e
)
P a rtia l re s p o n s e
S ta b le d is e a s e
P ro g re s s io n
6 p ts w ith o u t C T a s s e s s m e n t a re n o t s h o w n
+ C o n tin u in g tre a tm e n t
+
+
+ +
+
+ +
+
+
+
+
Median number of metastatic
chemo lines: 2
Median number of prior
metastatic lines: 5
Local Response Evaluation by RECIST1.1
Objective response rate
CR
PR
31% (17/54)
0
17
Clinical benefit rate
(CR+PR+SD ≥6 months)
48% (26/54)
BasedFonFLocalFAssessmentF
usingFRECISTF1.1F
MedianFPFS,FmonthsFF 6.8F
(95%FCI)F (4.6,F8.9)FF
Bardia et al, ASCO 2018
TROPiCS-02: Phase III Study mHER2-/HR+ mBC
At least two prior lines of chemotherapy
N=400; 1:1 randomization
Rugo, PI
55. ADC Characteristic Differences Between
T-DXd and T-DM1
T-DXd1-4,a ADC Attributes T-DM13-5
Topoisomerase I
inhibitor
Payload MoA Anti-microtubule
~8:1 Drug-to-antibody ratio ~3.5:1
Yes
Tumor-selective cleavable
linker?
No
Yes
Evidence of bystander
anti-tumor effect?
No
Trastuzumab
deruxtecan
(T-DXd)1
Trastuzumab
emtansine
(T-DM1)5
ADC, antibody-drug conjugate; MoA, mechanism of action.
aThe clinical relevance of these features is under investigation.
1. Nakada T et al. Chem Pharm Bull (Tokyo). 2019;67:173-85. 2. Ogitani Y et al. Clin Cancer Res. 2016;22:5097-108. 3. Trail PA et al. Pharmacol Ther. 2018;181:126-42.
4. Ogitani Y et al. Cancer Sci. 2016;107:1039-46. 5. LoRusso PM et al. Clin Cancer Res. 2011;17:6437-47.
57. Adverse Events of Special Interest
Adjudicated as drug-related ILD/pneumonitisa, n (%)
n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade
T-DXd (n = 257) 7 (2.7) 18 (7.0) 2 (0.8) 0 0 27 (10.5)
T-DM1 (n = 261) 4 (1.5) 1 (0.4) 0 0 0 5 (1.9)
• There were no grade 4 or 5 adjudicated drug-related ILD/pneumonitis events observed with T-DXd
LVEF, left-ventricular ejection fraction.
aPatients with prior history of ILD/pneumonitis requiring steroids were excluded. bLeft ventricular dysfunction. cDecreased ejection fraction.
LVEF decrease, n (%)
n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade
T-DXd (n = 257) 1 (0.4)b 6 (2.3)c 0 0 0 7 (2.7)
T-DM1 (n = 261) 0 1 (0.4)c 0 0 0 1 (0.4)
• In the T-DXd arm, all reported adverse events of LVEF decrease were asymptomatic and no cases of cardiac failure
occurred
58. Drug-Related TEAEs in ≥20% of Patients
System Organ Class
Preferred term, n (%)
T-DXd (n = 257) T-DM1 (n = 261)
Any Grade Grade ≥3 Any Grade Grade ≥3
Blood and lymphatic system disorders
Neutropeniaa 110 (42.8) 49 (19.1) 29 (11.1) 8 (3.1)
Anemiab 78 (30.4) 15 (5.8) 37 (14.2) 11 (4.2)
Leukopeniac 77 (30.0) 17 (6.6) 20 (7.7) 1 (0.4)
Thrombocytopeniad 64 (24.9) 18 (7.0) 135 (51.7) 65 (24.9)
Gastrointestinal disorders
Nausea 187 (72.8) 17 (6.6) 72 (27.6) 1 (0.4)
Vomiting 113 (44.0) 4 (1.6) 15 (5.7) 1 (0.4)
Diarrhea 61 (23.7) 1 (0.4) 10 (3.8) 1 (0.4)
Constipation 58 (22.6) 0 25 (9.6) 0
General disorders
Fatiguee 115 (44.7) 13 (5.1) 77 (29.5) 2 (0.8)
Investigations
AST increased 60 (23.3) 2 (0.8) 97 (37.2) 13 (5.0)
ALT increased 50 (19.5) 4 (1.6) 71 (27.2) 12 (4.6)
Metabolism and nutrition disorders
Decreased appetite 67 (26.1) 3 (1.2) 33 (12.6) 0
Skin and subcutaneous tissue disorders
Alopeciaf 93 (36.2) 1 (0.4) 6 (2.3) 0
Most drug-related TEAEs were gastrointestinal or hematological in nature
Adverse events were managed according to the protocol.
aThis category includes the preferred terms neutrophil count decreased and neutropenia. bThis category includes the preferred terms hemoglobin decreased, red blood cell count
decreased, anemia, and hematocrit decreased. cThis category includes the preferred terms white blood cell count decreased and leukopenia. dThis category includes platelet count
decreased and thrombocytopenia. eThis category includes the preferred terms fatigue, asthenia, and malaise. fGrade 1 alopecia: T-DXd = 26.5%, T-DM1 = 2.3%; grade 2, T-DXd = 9.3%.
59. Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
Schettini et al, NPJ Breast Cancer 2021
N=1576 N=1137
N=325
N=701
N=437
N=673
HER2 neg HR pos Triple Negative
IHC 1+
IHC 0 IHC 2+not amplified
HER2 IHC examples
HER2+
HER2-low
HER2-
Prevalence of HER2 Low
60. HER2-Low Breast Cancer defined as breast cancer with low levels of HER2 expression (ie, IHC 1+ or 2+/ISH-negative)
Trastuzumab Deruxtecan Has Clinical Activity in
HER2-low MBC
Modi S et al. J Clin Oncol. 2020.
Confirmed ORR = 44.4%
DESTINY-Breast04
HER2-low, unresectable and/or
metatastic breast cancer vs.
physician’s choice
NCT03734029*
2018-003069-33
Completed
Accrual
61. Circulating free payload is negligible due to high stability of the linker, thereby limiting
systemic exposure or nontargeted delivery of the payload
High-potency membrane-permeable payload (DXd) that requires TROP2-mediated
internalization for release
DS-1062 has a DAR of 4 for optimized therapeutic index2
DS-1062 has a substantially longer half-life than SG (≈ 5 days vs 11-14 hours),
enabling a more optimal dosing regimen
SG’s DLT is neutropenia, while DS-1062’s DLTs are maculopapular rash and
stomatitis/mucosal inflammation
Datopotomab Deruxtecan (Dato-DXd): TROP2 ADC IN
DEVELOPMENT
62. TROPION-PanTumor01: Dato-DXd TNBC Cohort
Antitumor Activity (by BICR)
BICR, blinded independent central review; CR, complete response; PD, progressive disease; PR, partial response; SoD, sum of diameters.
a Includes response evaluable patients who had ≥1 postbaseline tumor assessment or discontinued treatment. Postbaseline tumor assessments were not yet
available for 3 patients at the data cutoff. One patient was not confirmed to have a target lesion per BICR and therefore had a best overall response of
non-CR/non-PD; b Includes patients with a best overall response of CR, PR, stable disease, or non-CR/non-PD.
Data cutoff: January 8, 2021
Patients, n (%)a N=21
Objective response rate 9 (43)
CR/PR (confirmed) 5 (24)
CR/PR (pending confirmation) 4 (19)
Disease control rateb 20 (95)
Progressive disease 1 (5)
■ 6 mg/kg
■ 8 mg/kg
Change
in
SoD
of
target
lesions
over
time,
%
Months
-100
-80
-60
-40
-20
0
20
40
60
100
80
1 2 3 4
6 mg/kg
8 mg/kg
80
60
40
20
0
-20
-40
-60
-80
-100
Best
change
in
SoD,
%
Bardia et al, 2021
63. New ADCs against HER3:
Patritumab deruxtecan (U3-1402)
Study in progress: Phase I/II study of patritumab deruxtecan in HER3-positive BC (NCT02980341)
HER3-high HR+/HER2- mBC
HER3-low,
HR+/HER2-mBC
6.4 mg/kg
(n=21)
HER3-high TNBC
6.4 mg/kg
(n=31)
4.8 mg/kg
(n=33)
6.4 mg/kg
(n=31)
ORR (95% CI), % 30.3 (15.6–48.7) 12.9 (3.6–29.8) 33.3 (14.6–57.0) 16.1 (5.5–33.7)
mDOR (95% CI), mo 5.0 (2.8–NE) 7.2 (5.5–7.2) 5.3 (3.0–NE) NR (4.2–NE)
DCR (95% CI), % 90.9 (75.7–98.1) 74.2 (55.4–88.1) 66.7 (43.0–85.4) 83.9 (66.3–94.5)
mPFS(95% CI), mo 8.4 (5.6–9.9) 2.8 (1.9–8.2) 5.8 (1.4–11.0) 5.5 (3.9–NE)
mOS (95% CI), mo 14.3 (10.9–NE) 9.7 (6.6–19.5) 9.2 (4.7–21.9) NR (6.4–NE)
Patient population
HER3-high, HR+/HER2- mBC (n≈60)
HER3-low, HR+/HER2- mBC (n≈20)
HER3-high TNBC (n≈30)
HER3-DXd dose
4.8 mg/kg IV Q3W
6.4 mg/kg IV Q3W
6.4 mg/kg IV Q3W
6.4 mg/kg IV Q3W
Krop I, et al. Presented at SABCS 2020. Abstract PD1-09
64. Ladiratuzumab Vedotin: ADC Targeting LIV1
Anti-LIV1 mAB
Protease-cleavable
linker
MMAE
microtubule
disrupting
agent
LIV1 is a transmembrane cell adhesion molecule
highly expressed in metastatic breast cancer
Mech. of Action:
1. Binds to antigen
2. Complex internalized and trafficked to lysosome
3. Release of MMAE payload
4. Microtubule disruption
5. Cell cycle arrest/disruption
Phase I Study of Ladiratuzumab Vedotin
Confirmed ORR = 25% (15/60)
Modi S, et al. SABCS. 2017.
Next steps:
Weekly therapy to reduce toxicity
65. ADCS: The New Wave
• ADCs are an exciting and effective new therapy for mBC with evolving studies
• Established role in TNBC, HER2+ disease
◦ SG is a new standard of care for mTNBC
- Ongoing TROPiCS-02 trial in HR+ MBC
- Post-neoadjuvant SASCIA trial
◦ Dato-DXd is a new anti-TROP2 ADC
- Phase III studies in HR+ and TNBC
◦ T-DXd is a new standard of care for mHER2+ BC
- Ongoing Destiny Breast-04 in HER2 low disease
- Multiple trials in mHER2+ disease, CNS mets, post-neoadjuvant in HER2+
◦ New data with SYD985 for mHER2+ BC
• Studies are ongoing or are planned in combination with immunotherapy and in
early-stage disease
66. BEGONIA Trial
• First-line therapy for metastatic
TNBC
• Basket trial
• Arm 1: Durvalumab and weekly
paclitaxel
• Arm 6: Durvalumab and T-DXd
(also had to be HER2 low)
• PD-L1 testing using SP263
• Safety
• Arm 6: 2 cases of ILD
• Grade 2 and 3
• Both discontinued T-DXd
ARM 1; n=23
ARM 6; n=18
Schmid et al, Abstract 1023 ASCO 2021
67. 68
FUTURE-C-PLUS: PD1-blockade/anti-VEGF/taxane in immunogenicTNBC
Yin et al. Breast Cancer Res
2020
FUSCC classification (Fudan University Shanghai Cancer
Center)
FUTURE-trial, Jiang et al. Cell Research
2021
ORR 81%
Shao et al, ASCO 2021; slide provided by M. Kok
68. MEDIOLA: Schema for Third Stage
PI: Domchek, OT3-5-03, SABCS 2018
PI: Rugo
KEYLYNK-009
69. Examples of Other Combination Trials
• Phase II NIMBUS trial: nivolumab plus ipilimumab in metastatic,
hypermutated HER2neg breast cancer (DFCI)
• Checkpoint inhibitors combined with various ADCs in TN or HER2 low (SG,
TDXd)
• Amplifying the host immune response with radiation therapy
Asna et al, Curr Oncol 2018
70. Roadmap for Metastatic TNBC
Metastatic TNBC
Pembrolizumab + nab-
paclitaxel or paclitaxel*
Chemotherapy
PD-L1+
Sacituzumab
Govitecan
Pembrolizumab (CPS) or atezolizumab ex US (SP142), nab-paclitaxel only)
PARPi: PARP inhibitor (olaparib, talazoparib)
PD-L1-
Pembrolizumab +
gemcitabine/carboplatin
PARPi
Always consider clinical trials at each decision point
Novel ADCs
Checkpoint
inhibitor
Chemotherapy
Clinical trials
Clinical trials
First line Second line
PARPi
BRCA
mutation
