CCO Conference Highlights From the

2020 SABCS Virtual Symposium

CCO Independent Conference Highlights*

of the 2020 SABCS Annual Meeting, December 8-12, 2020

*CCO is an independent medical education company that provides state-of-the-art medical information to
healthcare professionals through conference coverage and other educational programs.

Supported by educational grants from Novartis Pharmaceuticals Corporation;

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Faculty
Sara Hurvitz, MD, FACP Joyce O’Shaughnessy, MD
Professor of Medicine Celebrating Women Chair in Breast
Director, Breast Oncology Program Cancer Research
Division of Hematology-Oncology Director, Breast Cancer Research
Department of Medicine Program
David Geffen School of Medicine at UCLA Baylor University Medical Center
Los Angeles, California Texas Oncology
US Oncology Network
Dallas, Texas
Faculty Disclosures
Sara Hurvitz, MD, FACP, has disclosed that she has received funds for research
support (paid to institution) from Ambrx, Amgen, Arvinas, Bayer, Daiichi
Sankyo, Dignitana, Genentech, GlaxoSmithKline, Immunomedics, Lilly,
MacroGenics, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Radius, Roche, Sanofi,
Seattle Genetics, and Zymeworks and funds for travel support from Lilly.
Joyce O’Shaughnessy, MD, has disclosed that she has received consulting fees
from AstraZeneca, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics.
Advances in the Treatment of
Early Breast Cancer
 CDK4/6 Inhibition in
High-Risk HR+/HER2- EBC
 monarchE: Adjuvant Abemaciclib + ET in High-Risk,
Node-Positive, HR+/HER2- EBC
 International, randomized, open-label phase III trial
Stratified by prior CT, menopausal
ITT Population (Cohorts 1 + 2) status, region

Women or men with high-risk, Cohort 1 Abemaciclib 150 mg BID up to 2 yrs +

node-positive, HR+/HER2- EBC; ≥ 4 positive ALN or 1-3 positive ET per standard of care of physician’s
prior (neo)adjuvant CT permitted; ALN plus histologic grade 3 choice for 5-10 yrs as clinically indicated
pre- or postmenopausal and/or tumor ≥ 5 cm (n = 2808)
no distant metastasis;
≤ 16 mos from surgery to Cohort 2
ET per standard of care of physician’s
randomization; ≤ 12 wks of ET 1-3 positive ALN, Ki-67 ≥ 20%
choice for 5-10 yrs as clinically indicated
after last non-ET per central testing, not grade
(n = 2829)
(N = 5637) 3, tumor size < 5 cm

 Primary endpoint: iDFS

‒ Planned for after ~ 390 iDFS events (~ 85% power, assumed iDFS HR of 0.73, cumulative 2-sided α = 0.05)
‒ Current primary outcome efficacy analysis occurred after 395 iDFS events in ITT population
 Key secondary endpoints: iDFS in Ki-67 high (≥ 20%) population, distant RFS, OS, safety, PRO, PK
Johnston. JCO. 2020;38:3987. Rastogi. SABCS 2020. Abstr GS1-01. Slide credit: clinicaloptions.com
 monarchE: Baseline Characteristics
Abemaciclib + ET ET Alone Abemaciclib + ET ET Alone
Characteristic Characteristic, %
(n = 2808) (n = 2829) (n = 2808) (n = 2829)

Median age, yrs (range) 51 (23-89) 51 (22-86) Pathologic tumor size

 < 65 84.4 85.4  < 2 cm 27.8 27.0
 ≥ 65 15.6 14.6  2-5 cm 48.8 50.2
 ≥ 5 cm 21.7 21.6
North America and
52.4/20.4/27.2 52.3/20.6/27.1
Europe/Asia/other, % Histologic grade at diagnosis
Pre/postmenopausal, % 43.5/56.5 43.5/56.5  1 7.4 7.6
 2 48.9 49.3
Prior CT, %  3 38.8 37.7
 Neoadjuvant  Not assessed 4.5 4.9
37.0 37.0
 Adjuvant 58.5 58.2
 None Ki-67 index < 20/≥ 20 33.9/44.9 34.4/43.6
4.5 4.7
Prior neoadjuvant/ TNM stage (derived)
adjuvant RT, % 2.5/93.3 2.9/92.9  IA
 IIA 0.1 0
 IIB 11.5 12.5
Positive axillary LN, % 13.9 13.7
 0  IIIA
0.2 0.2  IIIB 36.6 36.2
 1-3 39.9 40.4 3.7 3.2
 ≥4  IIIC
59.8 59.3 33.8 34.0
ER/PgR positive, % 99.1/86.2 99.2/86.7
Johnston. JCO. 2020;38:3987. Slide credit: clinicaloptions.com
 monarchE: iDFS (Primary Endpoint)
100  Patients with Ki-67
90 high tumors also
80
Abemaciclib + ET ET experienced
70 (n = 2808) (n = 2829) significant iDFS
60 Events, n 136 187 improvement with
iDFS (%)

50 2-yr iDFS, % 92.2 88.7 abemaciclib + ET vs ET

40
30 HR: 0.75 (95% CI: 0.60-0.93; P = .01) alone
20 ‒ HR: 0.70 (95% CI:
10 0.52-0.92; P = .01)
0
0 3 6 9 12 15 18 21 24 27 30 33
Patients
at Risk, n
Mos
Abe + ET 2808 2676 2613 2543 1996 1371 918 566 245 3 1 0 Median f/u: 19.1 mos in both arms.
ET 2829 2699 2649 2562 2013 1405 932 586 262 7 6 0 Curves should not be interpreted
beyond 24 mos due to limited f/u.

Johnston. JCO. 2020;38:3987. Rastogi. SABCS 2020. Abstr GS1-01. Slide credit: clinicaloptions.com
 monarchE: iDFS by Subgroup
Favors Favors
Abemaciclib + ET ET Alone Abemaciclib + ET ET Alone
Subgroup Analyzed No. Events No. Events HR (95% CI)
Overall 2808 136 2829 187 0.75 (0.60-0.93)
Region North America/Europe 1470 62 1479 89 0.72 (0.52-1.00)
Asia 574 28 582 30 0.93 (0.55-1.55)
Other 764 46 768 68 0.69 (0.48-1.00)
Menopausal status Premenopausal 1221 46 1232 72 0.63 (0.44-0.92)
Postmenopausal 1587 90 1597 115 0.82 (0.62-1.08)
Prior chemotherapy Neoadjuvant 1039 76 1048 111 0.69 (0.52-0.93)
Adjuvant 1642 52 1647 69 0.77 (0.54-1.10)
Age, yrs < 65 2371 111 2416 164 0.69 (0.54-0.88)
≥ 65 437 25 413 23 1.11 (0.63-1.96)
Race White 1947 93 1978 138 0.69 (0.53-0.90)
Asian 675 31 669 37 0.82 (0.51-1.33)
All others 146 11 140 11 1.04 (0.45-2.40)
Baseline ECOG PS 0 2405 110 2369 159 0.69 (0.54-0.88)
1 401 26 455 27 1.14 (0.66-1.95)
Primary tumor size, cm <2 780 31 765 48 0.63 (0.40-0.99)
2-5 1369 67 1419 86 0.83 (0.60-1.14)
≥5 610 35 612 52 0.68 (0.44-1.04)
No. of positive lymph nodes 1-3 1119 42 1143 60 0.71 (0.48-1.06)
4-9 1105 47 1125 72 0.69 (0.48-0.99)
10 575 45 554 55 0.79 (0.53-1.17)
Histologic grade G1 209 8 215 6 1.35 (0.47-3.89)
G2 1373 55 1395 81 0.71 (0.50-0.99)
G3 1090 67 1066 88 0.76 (0.55-1.04)
Progesterone receptor Negative 298 30 294 38 0.81 (0.50-1.30)
Positive 2421 104 2453 146 0.73 (0.57-0.94)
Tumor stage IIA 323 11 353 16 0.73 (0.34-1.57)
IIB 389 17 387 19 0.92 (0.48-1.78)
IIIA 1027 41 1024 61 0.68 (0.46-1.02)
IIIC 950 59 962 84 0.71 (0.51-0.99)

Johnston. JCO. 2020;38:3987. 0.5 1 2 3 Slide credit: clinicaloptions.com

 monarchE: Distant RFS
100  Most iDFS events
90 were distant
80
Abemaciclib + ET ET
recurrences (87 with
70 abemaciclib + ET vs
Distant RFS (%)

(n = 2808) (n = 2829)
60 138 with ET alone)
Events, n 106 152
50
2-yr iDFS, % 93.6 90.3
40  Common sites of
30 HR: 0.72 (95% CI: 0.56-0.92; P = .01)
distant recurrence
20
were bone, liver, and
10
0
lung
0 3 6 9 12 15 18 21 24 27 30 33
Patients
Mos
 Distant RFS benefit
at Risk, n
Abe + ET 2808
consistent across
2680 2619 2555 2005 1378 925 573 247 3 1 0
ET 2829 2704 2659 2576 2026 1417 941 590 263 7 6 0 subgroups
Median f/u: 19.1 mos in both arms. Curves should not
Johnston. JCO. 2020;38:3987. be interpreted beyond 24 mos due to limited f/u. Slide credit: clinicaloptions.com
 monarchE: Treatment-Emergent AEs
Abemaciclib + ET (n = 2791) ET (n = 2800)
Treatment-Emergent AE, n (%)
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Any AE 2731 (97.9) 1200 (43.0) 70 (2.5) 2410 (86.1) 335 (12.0) 19 (0.7)
 Diarrhea 2294 (82.2) 212 (7.6) 0 199 (7.1) 3 (0.1) 0
 Neutropenia 1246 (44.6) 501 (18.0) 18 (0.6) 141 (5.0) 16 (0.6) 3 (0.1)
 Fatigue 1073 (38.4) 78 (2.8) 0 433 (15.5) 4 (0.1) 0
 Leukopenia 1027 (36.8) 301 (10.8) 4 (0.1) 171 (6.1) 10 (0.4) 0
 Abdominal pain 948 (34.0) 37 (1.3) 0 227 (8.1) 9 (0.3) 0
 Nausea 779 (27.9) 13 (0.5) 0 223 (8.0) 1 (0) 0
 Anemia 638 (22.9) 47 (1.7) 1 (0) 90 (3.2) 9 (0.3) 1 (0)
 Arthralgia 571 (20.5) 6 (0.2) 0 876 (31.3) 18 (0.6) 0
 Hot flush 393 (14.1) 3 (0.1) 0 587 (21.0) 8 (0.3) 0
 Lymphopenia 372 (13.3) 140 (5.0) 2 (0.1) 94 (3.4) 13 (0.5) 0
 Thrombocytopenia 341 (12.2) 25 (0.9) 6 (0.2) 40 (1.4) 1 (0) 2 (0.1)
 Vomiting 455 (16.3) 13 (0.5) 0 117 (4.2) 2 (0.1) 0
 Headache 482 (17.3) 6 (0.2) 0 359 (12.8) 3 (0.1) 0
 Decreased appetite 312 (11.2) 15 (0.5) 0 54 (1.9) 1 (0) 0

Johnston. JCO. 2020;38:3987. Slide credit: clinicaloptions.com

 monarchE: Treatment-Emergent AEs of Special Interest
Abemaciclib + ET (n = 2791) ET (n = 2800)
Treatment-Emergent AE, n (%)
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
AST increase 257 (9.2) 43 (1.5) 3 (0.1) 106 (3.8) 13 (0.5) 0
ALT increase 265 (9.5) 59 (2.1) 5 (0.2) 119 (4.3) 16 (0.6) 0
Alopecia 254 (9.1) 0 0 53 (1.9) 0 0
Venous thromboembolic event 63 (2.3) 27 (1.0) 6 (0.2) 14 (0.5) 4 (0.1) 0
Interstitial lung disease 75 (2.7) 9 (0.3) 0 33 (1.2) 1 (0) 0

 14 patients (0.5%) died in each arm while on study treatment or within

30 days of discontinuation
‒ 11 patients in abemaciclib arm died due to AEs, 2 of which (diarrhea and
pneumonitis) were considered related to study treatment by investigator
‒ 7 patients in control arm died due to AEs
Johnston. JCO. 2020;38:3987. Slide credit: clinicaloptions.com
 PENELOPE-B: Palbociclib + ET in HR+/HER2- BC at
High Risk of Relapse After Neoadjuvant Chemotherapy
 Randomized, double-blind, placebo-controlled phase III trial
Stratified by age (≤ 50 vs > 50 yrs), nodal status (ypN0-1 vs ypN2-3), Ki-67
(> 15% vs ≤ 15%), region (Asia vs non-Asia), and CPS-EG score (≤ 3 vs 2 and ypN+)

Palbociclib 125 mg QD D1-21

Adult patients with confirmed 28-day cycles x 13
HR+/HER2- BC with residual + ET by local standard
disease after ≥ 16 wks of Surgery ± (n = 631) *Includes 6 wks of taxanes.
neoadjuvant CT*; †
Time between locoregional
radiotherapy†
CPS-EG score ≥ 3 or therapy and randomization:
Placebo QD D1-21 < 16 wks from final surgery
2 with ypN+
28-day cycles x 13 + or < 10 wks from RT
(N = 1250)
+ ET by local standard completion.
(n = 619)

 Primary endpoint: iDFS

 Secondary endpoints include: iDFS excluding second primary invasive non-breast cancers,
distant DFS, locoregional RFS, OS, safety, compliance, QoL
Loibl. SABCS 2020. Abstr GS1-02. Slide credit: clinicaloptions.com
 PENELOPE-B: Baseline Characteristics

Characteristic Palbociclib Placebo Characteristic Palbociclib Placebo

(n = 631) (n = 619) (n = 631) (n = 619)
Median age, yrs (range) 49 (22-76) 48 (19-79) Tumor stage at surgery, %
 ≤ 50 yrs, % 55.9 56.2  ypT0-1 37.7 33.7
 ypT2-3 58.3 62.9
Histological lymph node  ypT4 4.0 3.4
status at surgery, %
 ypN0-1 49.1 50.1 Lobular histology, % 9.2 8.5
 ypN2-3 50.9 49.9
G3 grading, % 46.7 48.1
Ki-67 >15% by central
25.5 25.5 Ovarian ablation, % 17.1 18.3
pathology, %
CPS-EG score, % Tamoxifen, % 49.8 49.8
 2 and ypN+ 40.1 41.2
 ≥3 59.9 58.8

Loibl. SABCS 2020. Abstr GS1-02. Slide credit: clinicaloptions.com

 PENELOPE-B: iDFS (Primary Endpoint)
2-Yr iDFS
100 88.3% 3-Yr iDFS  Median f/u: 42.8 mos
81.2% 4-Yr iDFS
73.0%
 Types of iDFS events
80
84.0% – 74% distant recurrences
77.7%
72.4%
60 – 116 with palbociclib,
iDFS (%)

iDFS
Events, n 111 with placebo
40 Palbociclib + ET 152
Placebo + ET 156 – 16% invasive
HR: 0.93 (95% CI: 0.74-1.17; P = .525) locoregional recurrences
20
– 21 with palbociclib, 27
+ Censored with placebo
0
Patients at 0 12 24 36 48 60 72
Risk, n Mos
Palbociclib 631 571 528 389 169 38 0
Placebo 619 553 497 349 161 24 1
Loibl. SABCS 2020. Abstr GS1-02. Reproduced with permission. Slide credit: clinicaloptions.com
 PENELOPE-B: iDFS by Subgroup
Subgroup Patients, n HR HR (95% CI) P Value Interaction Test
Overall 1250 0.931 (0.744-1.16) .532
ypN 0-1 620 0.974 (0.696-1.36) .880 .714
2-3 630 0.891 (0.660-1.20) .451
Age, yrs ≤ 50 701 0.955 (0.709-1.29) .764 .795
> 50 549 0.899 (0.641-1.26) .539
Ki-67 ≤ 15% 931 0.873 (0.654-1.16) .355 .504
> 15% 319 1.02 (0.718-1.46) .895
Risk status CPS-EG score 2 and ypN+ 508 0.798 (0.534-1.19) .272 .389
CPS-EG score ≥ 3 742 0.996 (0.760-1.30) .976
Geographical region Non-Asian 1155 0.943 (0.749-1.19) .619 .833
Asian 95 0.836 (0.339-2.06) .697
CPS-EG score 1/2 497 0.810 (0.539-1.22) .311 .674
3 561 0.958 (0.697-1.31) .789
4/5 192 1.08 (0.648-1.79) .772
First ET Tamoxifen ± OFS 622 0.942 (0.698-1.27) .698 .924
AI ± OFS 628 0.927 (0.661-1.30) .659
Duration of CT Shorter (≤ 20 wks) 594 0.867 (0.621-1.21) .401 .596
Longer (> 20 wks) 656 0.982 (0.726-1.33) .904
Type of surgery Breast conserving 432 0.893 (0.580-1.37) .605 .716
Mastectomy 818 0.956 (0.736-1.24) .738
Overall response to NACT CR or PR 1050 0.876 (0.683-1.12) .297 .346
SD or PD 200 1.16 (0.682-1.98) .579

0.3 0.5 0.8 1 1.5 2 2.5

Favors Favors Placebo
Loibl. SABCS 2020. Abstr GS1-02. Reproduced with permission. Palbociclib Slide credit: clinicaloptions.com
 PENELOPE-B: OS Interim Analysis
2-Yr OS
96.3% 3-Yr OS 4-Yr OS  Median follow-up:
100 93.6%
90.4%
94.5%
42.8 mos
80 90.5% 87.3%

60 OS
OS (%)

Events, n
Palbociclib + ET 62
40 Placebo + ET 69
HR: 0.87 (95% CI: 0.61-1.22; P = .420)
20
+ Censored
Patients at
0
0 12 24 36 48 60 72
Risk, n Mos
Palbociclib 631 596 574 442 206 46 1
Placebo 619 588 554 410 190 32 3

Loibl. SABCS 2020. Abstr GS1-02. Reproduced with permission. Slide credit: clinicaloptions.com
 PENELOPE-B: Patient Disposition and Exposure
Palbociclib Placebo Palbociclib Placebo
Patient Disposition (n = 631) (n = 619) Exposure Parameter P Value
(n = 633) (n = 611)
Started treatment, n 628 616
Duration of exposure,
Completed ≥ 7 cycles of tx, n (%) 559 (88.6) 559 (90.3) wks
 Mean 48.6 48.1 < .001
Completed all 13 tx cycles regularly, n  Median 52.9 52.0
(%) 508 (80.5) 523 (84.5)
 Range 1.1-70.1 1.4-66.0
Discontinued ET prematurely, n (%) 28 (4.4) 36 (5.8)
Relative total dose
Discontinued study tx, % 123 (19.5) 96 (15.5) intensity, %
 Disease recurrence 24 (4.0) 40 (6.5)  Mean 75.8 93.0 < .001
 Second primary non-breast cancer 2 (0.3) 3 (0.5)  Median 82.1 98.9
 Death 2 (0.3) 1 (0.2)  Range 0.4-105.9 0.7-104.3
 Adverse event 33 (5.2) 5 (0.8)
 Patient choice 56 (8.9) 41 (6.6)
 Investigator choice 5 (0.8) 6 (1.0)

Loibl. SABCS 2020. Abstr GS1-02. Slide credit: clinicaloptions.com

 CDK4/6 Inhibition in High-Risk HR+/HER2- EBC:
Summary
 monarchE: In a preplanned interim analysis, adj abemaciclib + ET continued to
demonstrate improved iDFS vs ET alone for HR+/HER2- EBC at high risk of relapse
after locoregional tx and/or (neo)adj CT (HR: 0.75; 95% CI: 0.60-0.93; P = .01)[1,2]
‒ 2-yr iDFS rates: 92.2% with abemaciclib + ET vs 88.7% with ET
‒ Significant iDFS improvement observed in Ki-67 high (≥ 20%) tumors
‒ Distant RFP also improved (HR: 0.72; 95% CI: 0.56-0.92; P = .01), with 2-yr distant RPF
rates of 93.6% vs 90.3%, respectively
 PENELOPE-B: In the first interim analysis, the addition of 1 yr of adjuvant
palbociclib to ET in the curative setting failed to demonstrate a benefit in patients
with higher-risk HR+/HER2- EBC after locoregional tx and neoadj CT[3]

1. Johnston. JCO. 2020;38:3987. 2. Rastogi. SABCS 2020. Abstr GS1-01. 3. Loibl. SABCS 2020. Abstr GS1-02. Slide credit: clinicaloptions.com
Treatment De-Escalation Strategies
in HR+/HER2- EBC
 PRIME II 10-Yr Update: Adjuvant Endocrine Therapy ±
Radiotherapy After Surgery in EBC
 Multicenter, randomized phase III trial[1,2]
Stratified by center
Adjuvant Endocrine Therapy +
Patients ≥ 65 yrs with histologically
Whole-Breast Irradiation
confirmed unilateral invasive
40-50 Gy in 15-25 fractions
ER+ or PgR+ EBC;
(n = 658)
received breast conserving surgery 10-Yr
(pN0) with tumor pathology ≤ 3 cm and Follow up
excision margin ≥ 1 mm;
receiving adjuvant ET Adjuvant Endocrine Therapy
(N = 1326) (n = 668)

 Primary endpoint: ipsilateral breast tumor  Secondary endpoints: regional

recurrence rates recurrence, contralateral BC, distant
‒ After 5-yr median f/u, recurrence was 1.3%
recurrence, DFS, OS
with RT and 4.1% without RT (P = .0002)[1]
1. Kunkler. Lancet Oncol. 2015;16:266. 2. Kunkler. SABCS 2020. Abstr GS2-03. Slide credit: clinicaloptions.com
 PRIME II 10-Yr Update: Baseline Characteristics

Characteristic, % No Radiotherapy Radiotherapy

(n = 668) (n = 658)
Mean age, yrs (SD) 71.12 (4.96) 70.78 (4.74)
Tumor size, %
 0-10.0 mm 38.6 40.3
 10.1-20.0 mm 48.8 48.5
 20.1-30.0 mm 12.6 11.2

Grade, %
1 40.9 44.4
2 55.6 54.6
3 3.5 2.0
Lymphovascular invasion, % 4.8 4.1
Preoperative endocrine therapy, % 9.1 8.3

Kunkler. SABCS 2020. Abstr GS2-03. Slide credit: clinicaloptions.com

 PRIME II 10-Yr Update: Efficacy Outcomes
Characteristic, % No Radiotherapy Radiotherapy P Value
(n = 668) (n = 658)
Local control at 10 yrs, n 43 5 .00008
 10-yr actuarial rate, % 9.8 0.9

Recurrence, n (%)
 Regional 13 (2.3) 3 (0.5) .014
 Distant 8 (1.9) 15 (3.6) .07
 Contralateral breast cancer 7 (1.2) 11 (2.2) .20
 New (nonbreast) cancer 49 (10.2) 40 (8.7) .41

Deaths, n 89 81 .68
 10-yr actuarial rate, % 80.4 81.0
10-yr metastasis-free survival, % (95% CI) 98.1 (96.7-99.6) 96.4 (94.5-98.4) .28

Cause of death, n (%)

 Cancer 35 (39) 29 (37)
• Breast cancer 8 (9) 3 (4) --
 Cardiovascular causes 9 (10) 14 (18)
 Other/unknown 44 (50) 36 (45)

Median follow-up: 7.3 yrs.

Kunkler. SABCS 2020. Abstr GS2-03. Slide credit: clinicaloptions.com
 RxPONDER: Adjuvant ET ± Chemotherapy in HR+/HER2-
EBC With 1-3 Positive Lymph Nodes and RS ≤ 25
 Randomized phase III trial
Stratified by RS score (0-13 vs 14-25), menopausal status
(pre vs post), axillary surgery (ALND vs SLNB)

Adults with HR+/HER2- EBC and

1-3 positive LN without distant mets*; Chemotherapy followed by ET Baseline
able to receive adjuvant taxane (n = 2509) characteristics
and/or anthracycline-based CT†; generally well
axillary staging by SLNB or ALND; ET alone balanced between
RS 0-25‡ (n = 2506) treatment arms
(N = 5015)
*Protocol amended to exclude patients with pN1mic as only nodal disease after 2493 patients
randomized. †Approved CT regimens: TC, FAC (or FEC), AC/T (or EC/T), FAC/T (or FEC/T); AC alone or
CMF not allowed. ‡Patients with RS > 25 recommended to be treated with CT followed ET off study.

 Primary endpoint: iDFS

 Key secondary endpoints: OS, distant DFS, local DFI, toxicity, QoL
Kalinisky. SABCS 2020. Abstr GS3-00. Slide credit: clinicaloptions.com
 RxPONDER: iDFS (Primary Endpoint)
 In this population with RS 0-25, RS did iDFS in Overall Population
not predict relative CT benefit for iDFS 1.0

0.8
‒ HR: 1.02 (95% CI: 0.98-1.06; P = .30)

iDFS Probability
CT + ET ET
0.6 (n = 2509) (n = 2506)
 CT use and RS independently Events 198 249
prognostic for iDFS 0.4
5-yr iDFS, % 92.4 91.0
0.2 Absolute difference, % 1.4
‒ iDFS events less likely among patients HR: 0.81 (95% CI: 0.67-0.98; P = .026)
who received CT 0
Patients at
0 1 2 3 4 5 6 7 8 9
‒ HR: 0.81 (95% CI: 0.67-0.96; P = .026) Risk, n Yrs Since Randomization
CT + ET 2509 2277 2104 1893 1648 1397 857 403 122 4
ET 2506 2327 2161 1910 1696 1404 846 397 135
‒ iDFS events more likely among 11

patients with higher RS  At median follow-up of 5.1 yrs, 447 iDFS

‒ HR: 1.06 (95% CI: 1.04-1.07; P < .001) events were observed (54% of expected
at final analysis)
Kalinisky. SABCS 2020. Abstr GS3-00. Reproduced with permission. Slide credit: clinicaloptions.com
 RxPONDER: Prespecified Analysis by Menopausal Status
Term HR 95% CI 2-Sided P Value
Chemotherapy 0.53 0.37-0.76 < .001
RS (per unit change) 1.06 1.04-1.08 < .001

Menopausal status 0.79 0.60-1.03 .08

Chemotherapy x menopause
interaction 1.79 1.17-2.74 .008

 Menopausal status influences chemotherapy benefit for iDFS

Kalinisky. SABCS 2020. Abstr GS3-00. Slide credit: clinicaloptions.com

 RxPONDER: Baseline Characteristics by
Menopausal Status
Postmenopausal Premenopausal Postmenopausal Premenopausal
Characteristic, % Characteristic, %
(n = 3350) (n = 1665) (n = 3350) (n = 1665)
Age group     Positive nodes    
 < 40 yrs 0.2 8.5 1 65.6 65.3
 40-49 yrs 1.9 60.8 2 25.1 25.7
 50-59 yrs 34.9 30.5 3 9.3 9.0
 60-69 yrs 45.7 0.2
 70+ yrs 17.3 0 Grade    
 Low 26.0 22.0
Recurrence score      Intermediate 63.5 68.3
 RS 0-13 44.8 38.7  High 10.6 9.7
 RS 14-25 55.2 61.3
Nodal dissection Tumor size    
   
 Full ALND 60.7 66.4  T1 59.1 56.2
 Sentinel LN only 39.3 33.6  T2/T3 41.9 43.9

Kalinisky. SABCS 2020. Abstr GS3-00. Slide credit: clinicaloptions.com

 RxPONDER: iDFS by Menopausal Status
Postmenopausal Premenopausal
1.0 1.0

0.8 0.8

iDFS Probability
iDFS Probability

CT + ET ET CT + ET ET
0.6 (n = 1675) (n = 1675) 0.6 (n = 834) (n = 831)

Events 147 158 Events 51 91

0.4 0.4
5-yr iDFS, % 91.6 91.9 5-yr iDFS, % 94.2 89.0
0.2 Absolute difference, % NS 0.2 Absolute difference, % 5.2
HR: 0.97 (95% CI: 0.78-1.22; P = .82) HR: 0.54 (95% CI: 0.38-0.76; P = .0004)
0 0
0 1 2 3 4 5 6 7 8 9 Patients at
0 1 2 3 4 5 6 7 8 9
Patients at
Risk, n Yrs Since Randomization Risk, n Yrs Since Randomization
CT + ET 1675 1514 1400 1268 1113 943 585 287 88 3 CT + ET 834 763 704 625 535 454 272 116 34 1
ET 1675 1567 1462 1308 1167 975 601 298 104 9 ET 831 760 699 602 529 429 245 99 31 2

 Absolute difference in distant recurrence as  Absolute difference in distant recurrence as

first site: 0.3% (2.3% CT + ET vs 2.6% ET) first site: 2.9% (3.1% CT + ET vs 6.0% ET)
Kalinisky. SABCS 2020. Abstr GS3-00. Reproduced with permission. Slide credit: clinicaloptions.com
 RxPONDER: iDFS by Menopausal Status
Across Subgroups
Subgroup Postmenopausal HR Interaction Subgroup Premenopausal HR Interaction
P Value P Value
Age ≥ 65 1.00 Age ≥ 50 0.84
Age 55-64 0.87 0.53 Age 45-49 0.43 0.25
Age < 55 1.24 Age < 45 0.44
Grade high 0.88 Grade high 1.06
Grade intermediate 1.05 0.80 Grade intermediate 0.49 0.28
Grade low 0.91 Grade low 0.44
Tumor size T3 1.22 Tumor size T3 0.25
Tumor size T2 0.96 0.92 Tumor size T2 0.62 0.54
Tumor size T1 0.95 Tumor size T1 0.48
3 Pos Nodes 1.36 3 Pos Nodes 0.47
0.55 0.79
2 Pos Nodes 1.00 2 Pos Nodes 0.62
1 Pos Nodes 0.90 1 Pos Nodes 0.50
Sentinel nodes 0.82 0.26 Sentinel nodes 0.49 0.69
Full axillary dis 1.08 Full axillary dis 0.57
RS 14-25 0.98 0.91 RS 14-25 0.56 0.57
RS 0-13 0.96 RS 0-13 0.45
Overall 0.97 Overall 0.54

0.5 0.75 1 1.5 2 0.25 0.5 0.75 1 1.5 2

CT + ET Better ET Better CT + ET Better ET Better
 Exploratory landmark analysis of 6-mo iDFS in premenopausal women on ET with OFS
(n = 126) vs no OFS (n = 647), HR: 0.73 (95% CI: 0.39-1.37; P = .33)
Kalinisky. SABCS 2020. Abstr GS3-00. Reproduced with permission. Slide credit: clinicaloptions.com
 RxPONDER: iDFS by RS and Menopausal Status
Postmenopausal CT + ET ET Premenopausal CT + ET ET
RS 0-13 n = 765 n = 736 RS 0-13 n = 311 n = 334
 Events, n 56 58  Events, n 10 25
 5-yr iDFS, % 93.4 92.9  5-yr iDFS, % 96.5 92.6
 Absolute diff, % NS  Absolute diff, % 3.9
 HR (95% CI) 0.96 (0.66-1.38); P = .81  HR (95% CI) 0.46 (0.22-0.97); P = .04
RS 14-25 n = 910 n = 939 RS 14-25 n = 523 n = 497
 Events, n 91 100  Events, n 41 66
 5-yr iDFS, % 90.1 91.2  5-yr iDFS, % 92.8 86.6
 Absolute diff, % NS  Absolute diff, % 6.2
 HR (95% CI) 0.98 (0.74-1.30; P = .89)  HR (95% CI) 0.57 (0.39-0.84); P = .005

Kalinisky. SABCS 2020. Abstr GS3-00. Slide credit: clinicaloptions.com

 RxPONDER: iDFS by Number of Nodes and
Menopausal Status
Postmenopausal CT + ET ET Premenopausal CT + ET ET
1 node n = 1090 n = 1099 1 node n = 536 n = 548
 iDFS Events, n 84 97  iDFS Events, n 29 61
 5-yr iDFS, % 92.7 92.3  5-yr iDFS, % 94.4 89.2
 Absolute diff, % NS  Absolute diff, % 5.2
 HR (95% CI) 0.90 (0.67-1.21); P = .49  HR (95% CI) 0.50 (0.32-0.77); P = .002
2-3 nodes n = 585 n = 576 2-3 nodes n = 298 n = 283
 iDFS Events, n 63 61  iDFS Events, n 22 30
 5-yr iDFS, % 89.3 91.2  5-yr iDFS, % 93.8 88.7
 Absolute diff, % NS  Absolute diff, % 5.1
 HR (95% CI) 1.09 (0.77-1.55); P = .63  HR (95% CI) 0.58 (0.34-1.02); P = .057

Kalinisky. SABCS 2020. Abstr GS3-00. Slide credit: clinicaloptions.com

 RxPONDER: OS by Menopausal Status
Postmenopausal Premenopausal
1.0 1.0

0.8 0.8
CT + ET ET CT + ET ET

OS Probability
OS Probability

0.6 (n = 1675) (n = 1675) (n = 834) (n = 831)

0.6
Deaths 76 83 Deaths 12 25
0.4 5-yr OS, % 96.2 96.1 0.4 5-yr OS, % 98.6 97.3
Absolute difference, % NS Absolute difference, % 1.3
0.2 HR: 0.96 (95% CI: 0.70-1.31; P = .79) 0.2 HR: 0.47 (95% CI: 0.24-0.94; P = .032)

0 0
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Patients at Patients at
Risk, n Yrs Since Randomization Risk, n Yrs Since Randomization
CT + ET 1675 1524 1418 1296 1156 988 618 313 98 4 CT + ET 834 768 714 642 552 473 290 126 39 1
ET 1675 1584 1484 1346 1213 1021 639 325 110 9 ET 831 772 722 635 565 467 275 117 34 2

Kalinisky. SABCS 2020. Abstr GS3-00. Reproduced with permission. Slide credit: clinicaloptions.com
 ADAPT HR+/HER2-: Adjuvant ET ± Chemotherapy in
Intermediate/High-Risk, HR+/HER2- Luminal EBC
 2-part, prospective phase III trial
‒ Part 1: Current analysis evaluated prognostic impact of RS < 26 and Ki-67 decrease after short-
course of preoperative ET in the ET alone arm and is not a randomized comparison
Adult patients
 pN2-3
with HR+/HER2- Baseline biopsy evaluated Chemotherapy followed by ET
 pN0-1/RS > 25
unilateral luminal EBC; for RS score (Oncotype Dx) (n = 2335)
 pN0-1/RS 12-25/
cT1-4c, cN0-3; and Ki-67 expression; Ki-67post > 10%
candidates for adjuvant CT surgical specimen evaluated
by conventional for Ki-67 expression† after
prognostic criteria*  pN0-1/RS 12-25/
short ET run-in ET alone
(N = 4691) Ki-67post ≤ 10%
(n = 2356)
*cT2 or G3 or Ki-67 ≥ 15% or < 35 yrs old or cN+.  pN0-1/RS 0-11
†
Ki-67post ≤ 10% = ET response.

 Primary endpoint: 5-yr iDFS  Key secondary endpoints: dDFS, OS,

translational research
‒ Part 1: noninferiority for pN0-1/RS 12-
25/Ki-67post ≤ 10% vs pN0-1/RS 0-11
Harbeck. SABCS 2020. Abstr GS4-04. Slide credit: clinicaloptions.com
 ADAPT HR+/HER2-: Baseline Characteristics
ITT Population of ET Alone Patients (n = 2290)
Characteristic pN0-1/RS 0-11 pN0-1/RS 12-25/ Ki-67post ≤ 10%
(n = 868) (n = 1422)
Median age, yrs 57 58
 ≤ 50 yrs of age, n (%) 260 (30.0) 332 (23.3)
Premenopausal status, n (%) 300 (34.6) 374 (26.3)
Tumor stage pT2-4, n (%) 300 (34.6) 543 (38.2)
Nodal status pN1, n (%) 208 (24.0) 389 (27.4)
Grade 3, n (%) 114 (13.1) 306 (21.5)
Median Ki-67, % 15 15
Positive PgR, n (%) 823 (94.8) 1251 (88.0)

 Median follow-up: 60 mos (range: 0-91)

Harbeck. SABCS 2020. Abstr GS4-04. Slide credit: clinicaloptions.com

 ADAPT HR+/HER2-: 5-Yr iDFS (Primary Endpoint)

100
 Primary endpoint met
─ 5-yr iDFS difference: -1.3%
80 (95% CI: -3.3% to 0.6%)
5-Yr iDFS, %
60 ─ 95% lower confidence limit of -3.3%
iDFS (%)

(95% CI)
RS 0-11 93.9 (91.8-95.4) met prespecified criterion for
40 RS 12-25/Ki-67 ≤ 10% 92.6 (90.8-94.0) noninferiority of pN0-1/RS
12-25/Ki-67post ≤ 10% vs pN0-1/RS 0-11
20
(P = .05)
0  5-yr OS rate
0 12 24 36 48 60
Patients at Risk, n
Mos F/u ─ 97.3% for pN0-1/RS 12-25/Ki-67
RS 0-11 865
RS 12-25/Ki-67 ≤ 10% 1414
796
1289
705
1124
657
1019
603
938
431
671
≤ 10% vs 98.0% for pN0-1/RS 0-11
(P = .160)
Harbeck. SABCS 2020. Abstr GS4-04. Reproduced with permission. Slide credit: clinicaloptions.com
 ADAPT HR+/HER2-: 5-Yr dDFS
5-yr dDFS, % pN0-1/RS 12-25/Ki-67 ≤ 10% pN0-1/RS 0-11 P Value
Overall population 95.6 96.3 .247
≤ 50 yrs of age 97.4 96.8 .896
> 50 yrs in age 95.1 96.1 .256
Node negative 96.6 96.8 .440
1-3 lymph nodes 92.7 94.6 .458
1 94.7 93.7 --
2 92.4 96.0 --
3 75.9 100 --

 5-yr dDFS subgroup analysis suggests that patients with RS 12-25 with
≥ 3 involved lymph nodes may not be ideal candidates for ET alone
Harbeck. SABCS 2020. Abstr GS4-04. Slide credit: clinicaloptions.com
 ADAPT HR+/HER2-: Univariable and Multivariable
Analyses of dDFS
Univariable Analysis Multivariable Analysis
Factor Type HR (95% CI) P Value Covariate/Factor Type HR (95% CI) P Value
pN0-1/RS12- pN0-1/RS12-
25/Ki-67post ≤ Binary 1.32 (0.82-2.13) .249 25/Ki-67post ≤ Binary NA NS
10% vs RS 0-11 10% vs RS 0-11
pN1 vs pN0 Binary 1.78 (1.12-2.83) .015 pN1 vs pN0 Binary NA NS
LN2-3 vs LN0-1 Binary 2.39 (1.26-4.52) .008 LN2-3 vs LN0-1 Binary NS
LN3 vs LN0-2 Binary 4.44 (1.79-10.99) .001 LN3 vs LN0-2 Binary 3.40 (1.35-8.53) .009
Grade 3 vs 1-2 Binary 1.54 (0.92-2.59) .102 Grade 3 vs 1-2 Binary NA NS
pT2-4 vs pT0-1 Binary 2.40 (1.53-3.76) < .001 pT2-4 vs pT0-1 Binary 2.24 (1.39-3.59) .001
> 50 vs ≤ 50 yrs Binary 1.44 (0.82-2.52) .209 > 50 vs ≤ 50 yrs Binary NA NS
of age of age
Continuous scale, Continuous scale,
Ki-67 baseline per 10% 1.33 (1.05-1.68) .018 Ki-67 baseline per 10% NA NS

Continuous scale, Continuous scale,

PgR baseline per 10% 0.91 (0.86-0.97) .003 PgR baseline per 10% 0.92 (0.86-0.98) .008

Continuous scale, Continuous scale,

ER baseline per 10% 1.02 (0.83-1.26) .853 ER baseline per 10% NA NS

Harbeck. SABCS 2020. Abstr GS4-04. Slide credit: clinicaloptions.com

 Treatment De-Escalation Strategies in HR+/HER2- EBC:
Summary
 Prime II: At 10 yrs of f/u, there was no significant OS difference in patients ≥ 65 yrs of age with
lower-risk HR+/HER2- EBC receiving ET with the omission of adj whole breast RT[1]
‒ 10-yr actuarial OS rate: 80.4% without RT vs 81.4% with RT; P = .68

‒ 10-yr actuarial IBTR rate was 9.8% with the omission of RT vs 0.9% with RT in these patients (P = .00008);
however, most deaths (93.4%) were not due to BC

 RxPONDER: In an interim analysis of adj CT for HR+/HER2- EBC with 1-3 positive nodes and RS ≤ 25,
postmenopausal women did not benefit, whereas premenopausal women did[2]
‒ Premenopausal patients experienced a 46% decrease in iDFS events and a 53% decrease in deaths, leading
to a 5-yr OS absolute improvement of 1.3%

 ADAPT HR+/HER2-: In the primary analysis of adj ET ± CT in intermediate or high-risk luminal BC

with 0-3 positive nodes, ET alone was noninferior to ET + CT in patients with RS 0-11 and in patients
with RS 12-25 and endocrine response (Ki-67post ≤ 10%)[3]
‒ 5-yr iDFS: 93.9% vs 92.6%, respectively; 5-yr dDFS: 96.3% vs 95.6%; 5-yr OS: 98.0% vs 97.3%
1. Kunkler. SABCS 2020. Abstr GS2-03. 2. Kalinisky. SABCS 2020. Abstr GS3-00. 3. Harbeck. SABCS 2020. Abstr GS4-04. Slide credit: clinicaloptions.com
Additional Studies in EBC
 ExteNET: Neratinib vs Placebo After Adjuvant
Trastuzumab in HER2+ EBC
 Multicenter, randomized phase III trial
Stratified by HR status (ER+ and/or PgR+ vs ER- and PgR-), nodal status (0 vs 1-3 vs ≥ 4), 1 Yr
adjuvant trastuzumab regimen (sequential vs concurrent with CT)

Patients with operable HER2+

EBC (stage I-IIIc), N+ or N- Neratinib 240 mg/day PO
disease, and adj trastuzumab (n = 1420)
Current report:
completed ≤ 2 yrs before final OS analysis
Placebo
randomization*
(n = 1420)
(N = 2840)
*Concurrent adj ET recommended for HR+ disease.

*Amendment in Feb 2010 restricted enrollment to higher-risk patients defined as

those with N+ disease who completed trastuzumab ≤ 1 yr before randomization.

 Primary endpoint: iDFS at 2 yrs

 Key secondary endpoints: OS, DFS-DCIS, DDFS, TTDR, CNS recurrence
Holmes. SABCS 2020. Abstr PD3-03. Martin. Lancet Oncol. 2017;18:1688. Chan. Lancet Oncol. 2016;17:367. NCT00878709. Slide credit: clinicaloptions.com
 ExteNET: OS (ITT Population)
2-Yr OS 5-Yr OS
98.4% 8-Yr OS
100 94.1%
98.1% 90.2% Δ -0.1%
93.3%
80 90.1%

OS (%) 60 Neratinib
Placebo
40

20
HR: 0.95 (95% CI: 0.75-1.21; P = .6914)
0
0 1 2 3 4 5 6 7 8 9 10
Patients at Risk, n Yrs After Randomization
Neratinib 1420 1364 1309 1213 1188 1168 1123 1041 746 218 0
Placebo 1420 1384 1341 1249 1223 1199 1166 1086 796 221 0

 Neratinib numerically improved OS in HR+ disease (8-yr OS rate: 91.6% vs 90.1%; HR: 0.8; 95% CI:
0.58-1.12) but not in HR- disease (8-yr OS rate: 88.1% vs 90.3%; HR: 1.18; 95% CI: 0.83-1.69)
Holmes. SABCS 2020. Abstr PD3-03. Reproduced with permission. Slide credit: clinicaloptions.com
 ExteNET: Summary of Descriptive Analyses
 Neratinib appears to be associated  Trend toward improved CNS
with improved OS in subgroups of outcomes in patients with HER2+ EBC
clinical interest receiving neratinib vs placebo
HR+ Disease/Trastuzumab Neratinib Placebo ‒ Lower cumulative incidence of CNS
Completion ≤ 1 Yr (n = 670) (n = 664)
recurrence in ITT (1.3% vs 1.8%) and
8-yr OS rate, % 91.5 89.4 HR+/≤ 1 yr (0.7% vs 2.1%) populations
HR (95% CI) 0.79 (0.55-1.13)
P value .203
‒ Improved 5-yr CNS disease-free
survival in ITT (HR: 0.73; 95% CI: 0.45-
HR+ Disease/Trastuzumab Neratinib Placebo 1.17) and HR+/≤ 1-yr (HR: 0.41; 95%
Completion ≤ 1 Yr/No pCR (n = 131) (n = 164)
CI: 0.18-0.85) populations
8-yr OS rate, % 91.3 82.2
HR (95% CI) 0.47 (0.23-0.92)
P value .031

Holmes. SABCS 2020. Abstr PD3-03. Slide credit: clinicaloptions.com

 I-SPY 2: Neoadjuvant Ladiratuzumab Vedotin vs
Paclitaxel in High-Risk HER2- Stage II/III EBC
 Multicenter phase II trial using response-adaptive randomization within molecular subtypes
as defined by receptor status and MammaPrint risk to test novel neoadjuvant therapies for
high-risk EBC vs common control arm
‒ Ladiratuzumab vedotin (SGN-LIV1A): investigational ADC targeting LIV-1 zinc transporter

Ladiratuzumab vedotin Doxorubicin/

2.5 mg/kg Q3W x 4 cycles Cyclophosphamide
Patients with Surgery,
high-risk HER2-,* (n = 60) 4 cycles
assessment
stage II/III EBC; for pCR
tumor size ≥ 2.5 cm† Paclitaxel Doxorubicin/
80 mg/m2 IV 12 wks Cyclophosphamide
(n = 327) 4 cycles
*If HR+, then must be high risk by MammaPrint. †Randomization to an investigational
arm based on probability of patient achieving pCR with given agent; 20% of I-SPY2
patients overall randomized to control arm. Serial MRI, biopsy, and blood draws done
 Primary endpoint: pCR during treatment phase.

Beckwith. SABCS 2020. Abstr PD1-10. Slide credit: clinicaloptions.com

 I-SPY 2 (Ladiratuzumab Vedotin): Pathologic CR

Estimated pCR Rate (95% CI)

Probability That
Predictive
Ladiratuzumab
EBC Subtype Vedotin Is Superior Probability of
Ladiratuzumab Paclitaxel Success in Phase III
Vedotin to Control

0.162 0.204
HER2- 0.177 0.023
(0.08-0.24) (0.16-0.25)
0.246 0.279
HR-/HER2- 0.310 0.064
(0.12-0.37) (0.21-0.35)
HR+/HER2- 0.09 0.141 0.154 0.030
(0-0.18) (0.09-0.19)

 Estimated pCR rates with ladiratuzumab vedotin are comparable to

paclitaxel across all evaluated EBC subtypes

Beckwith. SABCS 2020. Abstr PD1-10. Slide credit: clinicaloptions.com

 I-SPY 2 (Ladiratuzumab Vedotin):
pCR Probably Distributions
HER2- Prob(>Ctl) = 17.7% HR-/HER2- Prob(>Ctl) = 31% HR+/HER2- Prob(>Ctl) = 15.4%
Prob(Ph3) = 2.3% Prob(Ph3) = 6.4% Prob(Ph3) = 3%

Control: 20% Control: 14%

Control: 28%

Ladiratuzumab: 16% Ladiratuzumab: 25% Ladiratuzumab: 9%

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
16%-25% pCR rate pCR rate pCR rate
21%-35% 9%-19%
8%-24% 12%-37% 0%-18%
 Mean of each distribution is the estimated pCR rate
Beckwith. SABCS 2020. Abstr PD1-10. Reproduced with permission. Slide credit: clinicaloptions.com
 I-SPY 2 (Ladiratuzumab Vedotin): Safety
Ladiratuzumab Vedotin Paclitaxel
Grade 3/4 Adverse Events,* n (%)
(n = 60) (n = 327)
Hematologic
 Febrile neutropenia 4 (6.7) 22 (6.7)
 Neutropenia 9 (15) 34 (10.4)
Nonhematologic
 Alanine aminotransferase increased 11 (18.3) 6 (1.8)
 Aspartate aminotransferase increased 5 (8.3) 3 (0.9)
 Hyperglycemia 4 (6.7) 3 (0.9)
 Peripheral neuropathy 0 8 (2.4)

*From start of treatment to 30 days post surgery.

Beckwith. SABCS 2020. Abstr PD1-10. Slide credit: clinicaloptions.com

 Additional Studies in EBC: Summary
 ExteNET: In the final OS analysis, adjuvant neratinib after completion of
adjuvant trastuzumab did not significantly improve OS in patients with
HER2+ EBC (HR: 0.95; 95% CI: 0.75-1.21; P = .6914)[1]
‒ 8-yr OS rate: 90.2% with neratinib vs 90.1% with placebo
‒ However, trends toward longer OS in subgroups of clinical interest (eg, HR+
disease with trastuzumab completion ≤ 1 yr ± lack of pCR with neoadjuvant
therapy) and improved CNS outcomes with neratinib vs placebo
 I-SPY 2: Neoadjuvant treatment with ladiratuzumab vedotin followed by AC
in high-risk, stage II/III, HER2- EBC achieved a similar pCR rate as paclitaxel [2]

1. Holmes. SABCS 2020. Abstr PD3-03. 2. Beckwith. SABCS 2020. Abstr PD1-10. Slide credit: clinicaloptions.com
Advances in the Treatment of
HR+/HER2- MBC
Novel Chemotherapy for HR+/HER2- MBC
 CONTESSA: Tesetaxel + Capecitabine vs Capecitabine in
HR+/HER2- MBC With Prior Taxane
 Multicenter, open-label, randomized phase III trial[1]
‒ Tesetaxel: novel, oral taxane with antitumor activity in HR+/HER2- MBC[2]
Stratified by visceral disease; geographic region; no. of prior CT regimens for advanced BC

Tesetaxel 27 mg/m2 PO, Day 1

Patients with HR+/HER2- MBC and Capecitabine 825 mg/m2 PO BID, Days 1 (pm) to 15 (am)
measurable disease by RECIST v1.1; 21-day cycle
0-1 prior CT regimens for MBC; (n = 343) Until PD or
any no. prior ET or targeted tx; unacceptable
prior taxane (neo/adjuvant with toxicity
any DFI) required Capecitabine 1250 mg/m2 PO BID, Day 1 (pm) to 15 (am)
(N = 685) 21-day cycle
(n = 342)

 Primary endpoint: PFS by IRC (90% power to detect hazard ratio 0.71 on 347 expected events)
 Secondary endpoints: OS, ORR by IRC, DCR by IRC, safety
1. O’Shaughnessy. SABCS 2020. Abstr GS4-01. 2. Seidman. ASCO 2018. Abstr 1042. Slide credit: clinicaloptions.com
 CONTESSA: Baseline Characteristics
Tesetaxel + Capecitabine Tesetaxel +
Characteristic Capecitabine Capecitabine
(n = 342) Characteristic Capecitabine
(n = 343) (n = 343)
(n = 342)
Median age, yrs
56 (23-85) 57 (29-84) Prior CT regimens for
(range)
Median time from 5.1 5.2 MBC, %
diagnosis, yrs (range) (0.9-24.6) (0.8-24.0) 0 92 94
1 8 6
ECOG PS 0/1/2+, % 54/44/2 59/39/2
North America/ DFI after prior taxane
45/37/18 45/38/17 < 24 mos, % 33 32
Europe/Asia Pacific, %
Prior therapy, % Visceral disease, % 80 78
 Taxane 100 99
 Anthracycline 84 88 Common sites of
 Alkylator 93 92 metastatic disease, %
 ET 93 90  Bone 70 68
 CDK4/6 inhibitor 49 51  Liver 60 55
 Lung 38 34

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Slide credit: clinicaloptions.com

 CONTESSA: PFS by IRC
Tesetaxel + Cape Cape
100 (n = 343) (n = 342)
Events 155 169
80 Median PFS, mos 9.8 (8.4-12.0) 6.9 (5.6-8.3)
(95% CI)

60 Improvement, mos 2.9

PFS (%)

HR: 0.716 (95% CI: 0.573-0.895;

40 P = .003)

Tesetaxel + Capecitabine
20
Capecitabine
+ Censored
0
0 2 4 6 8 10 12 14 16 18 20 22 24 64
Patients at Risk, n Mos from Randomization
Tesetaxel + Cape 343 267 216 154 117 68 42 26 20 6 2 2 1 0
Cape 342 236 175 111 74 49 25 15 10 4 4 4 0 0

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Reproduced with permission. Slide credit: clinicaloptions.com
 CONTESSA: PFS by IRC Across Subgroups
HR (95% CI)
Characteristics HR (95% CI) P Value
Overall Treatment Group
All (N = 685) 0.72 (0.57-0.90) .003
Age (yrs)
< 65 (n = 531) 0.69 (0.53-0.88) .003
≥ 65 (n = 154) 0.72 (0.43-1.21) .217
Baseline ECOG PS
0 (n = 387) 0.62 (0.46-0.84) .002
≥ 1 (n = 297) 0.80 (0.58-1.12) .197
DFI Following Prior Taxane
< 24 mos (n = 226) 0.70 (0.48-1.02) .063
≥ 24 mos (n = 459) 0.69 (0.52-0.91) .009
Prior CDK4/6 Inhibitor
No (n = 345) 0.67 (0.49-0.92) .013
Yes (n = 340) 0.76 (0.55-1.04) .086
Visceral or CNS Disease
No (n = 145) 0.87 (0.48-1.57) .641
Yes (n = 540) 0.70 (0.55-0.89) .004
Geographic Region
North America/Western Europe (n = 456) 0.72 (0.54-0.94) .017
Rest of World (n = 229) 0.71 (0.48-1.04) .079

0.2 0.4 0.6 0.8 1.0 2.0 3.0 4.0 5.0

Favors Tesetaxel + Capecitabine Favors Capecitabine

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Reproduced with permission. Slide credit: clinicaloptions.com
 CONTESSA: Response
ORR by IRC* 24-Wk DCR† by IRC*
100 100
90 90
80 80 P < .0001
P = .0002
70 70 67%
60 57% 60

Patients (%)
Patients (%)

50%
50 50
41%
40 40
30 30
20 20
10 10
0 0
Tesetaxel + Capecitabine Tesetaxel + Capecitabine
Capecitabine (n = 283) Capecitabine (n = 283)
(n = 274) (n = 274)
*Patients with measurable disease. †DCR = ORR + SD.
O’Shaughnessy. SABCS 2020. Abstr GS4-01. Reproduced with permission. Slide credit: clinicaloptions.com
 CONTESSA: AEs
All-Grade TEAEs Occurring in Tesetaxel + Capecitabine Tesetaxel +
≥ 20% of Patients in Either Capecitabine Capecitabine Capecitabine
(n = 337) (n = 337)
Arm, % (n = 337) Grade 3/4 TEAEs (n = 337)
Hematologic Occurring in ≥ 5% of
 Neutropenia 76.9 22.6 Patients in Either Arm,
 Anemia 29.7 19.0 %
Grade 3 Grade 4 Grade 3 Grade 4
 Thrombocytopenia 20.5 6.2
GI
 Nausea 62.6 42.7
 Diarrhea 61.1 46.9 Hematologic
 Constipation 33.2 15.1  Neutropenia 32.6 38.3 7.4 0.9
 Vomiting 30.6 19.9  Febrile neutropenia 10.4 2.7 0.3 0.9
 Abdominal pain 21.7 17.2  Anemia 8.0 0 2.4 0
 Stomatitis 20.5 19.1  Leukopenia 6.8 3.0 0.6 0.3
Other
 Hand–foot syndrome 50.7 66.2 GI
 Neuropathy 48.1 13.6  Diarrhea 12.5 0.6 8.9 0
 Fatigue 47.8 34.4  Nausea 6.2 0 2.1 0
 Decreased appetite 28.8 19.3
 Alopecia* 28.2 2.4 Other
 Hypokalemia 20.5 6.8  Fatigue 8.6 0 4.5 0
 Hypokalemia 8.0 0.6 2.7 0
 Hand–foot 6.8 0 12.2 0
syndrome
*Grade 2 alopecia: 8.0% with tesetaxel + capecitabine vs 0.3% with
 Neuropathy
capecitabine 5.3
alone. No treatment-related 0.6 0.9reactions.0
hypersensitivity

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Slide credit: clinicaloptions.com

 CONTESSA: AEs Leading to Discontinuation

AEs Leading to Discontinuation in Tesetaxel + Capecitabine Capecitabine

≥ 1% Patients in Either Arm, % (n = 337) (n = 337)
Neutropenia/febrile neutropenia 4.2 1.5
Neuropathy 3.6 0.3
Sepsis/septic shock 1.8 0.6
Diarrhea 0.9 1.5
Hand–foot syndrome 0.6 2.1
Discontinuation to any AE* 23.1 11.9
*Treatment-related death occurred in 6 patients (5 sepsis, 1 cardiorespiratory arrest) receiving tesetaxel + capecitabine, and 3 patients (2 septic
shock, 1 colitis) receiving capecitabine alone.

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Slide credit: clinicaloptions.com

 Novel Chemotherapy for HR+/HER2- MBC:
Conclusions
 In the CONTESSA primary analysis, all-oral combination of tesetaxel +
capecitabine significantly improved PFS vs capecitabine alone in patients
with HR+/HER2- MBC who received prior taxane CT
‒ Median PFS: 9.8 vs 6.9 mos (HR: 0.716; 95% CI: 0.573-0.895; P = .003)
‒ PFS benefit consistent across analyzed subgroups
 Combination had generally manageable toxicity profile
‒ Dose reductions and G-CSF as needed
‒ Neutropenia was most frequent grade ≥ 3 treatment-emergent AE and led to
treatment discontinuation in 4.2% of patients vs 1.5% with capecitabine alone

O’Shaughnessy. SABCS 2020. Abstr GS4-01. Slide credit: clinicaloptions.com

Update on CDK4/6 Inhibition With Ribociclib
in HR+/HER2- MBC
 MONALEESA-7: Ribociclib + Endocrine Therapy in
HR+/HER2- Advanced Breast Cancer
 International, double-blind, randomized phase III trial[1-3]
Stratified by liver/lung mets (yes vs no), prior CT for advanced
disease (yes vs no), ET (tamoxifen + goserelin vs NSAI + goserelin)

Ribociclib 600 mg PO QD on Days 1-21 +

Goserelin 3.6 mg SC on Day 1 +
Pre/perimenopausal women with HR+/HER2- NSAI or Tamoxifen* PO QD on 28-day cycles
advanced breast cancer; ECOG PS ≤ 1; (n = 335)
≤ 1 line of prior CT for advanced disease; no prior ET
for advanced disease and no prior CDK4/6 inhibitor; Placebo PO QD on Days 1-21 +
(neo)adjuvant ET permitted Goserelin 3.6 mg SC on Day 1 +
(N = 672) NSAI or Tamoxifen* PO QD on 28-day cycles
(n = 337)
 Primary endpoint: PFS  Key secondary endpoint: OS
‒ Median PFS: 23.8 vs 13.0 mos (hazard ratio:  Median OS: NR vs 40.9 (hazard ratio: 0.71;
0.55; 95% CI: 0.44-0.69; P < .0001)[2] 95% CI: 0.54-0.95; P = 0.00973)[3]
*ET based on prior (neo)adjuvant or investigator/patient preference. NSAI either letrozole 2.5 mg or anastrozole 1 mg; tamoxifen at 20 mg.
1. Tripathy. SABCS 2020. Abstr PD2-04. 2. Tripathy. Lancet Oncol. 2018;19:904. 3. Im. NEJM. 2019; 381:3073. 3. Slide credit: clinicaloptions.com
 MONALEESA-7 Update: Patient Disposition
Patient disposition, % Ribociclib + ET Placebo + ET All Patients
(n = 335) (n = 337) (N = 672)
Patients treated 100 100 100
 Treatment ongoing* 21.2 9.2 15.2
 Ended treatment 78.8 90.8 84.8
Reason for end of treatment
 Progressive disease 62.7 73.6 68.2
 Patient/guardian decision 6.3 4.7 5.5
 Physician decision 3.6 7.4 5.5
 Adverse event 4.8 3.6 4.2
 Death 0.9 0.9 0.9
 Lost to follow-up 0.6 0 0.3
 Protocol deviation 0 0.6 0.3
Entered survival follow-up† 87.9 91.2 89.6

 Median follow-up: 53.5 mos (range: 46.9-66.4) *As of data cutoff: June 29, 2020. †Denominator:
number of patients who ended treatment (n = 264,
n = 306, and n = 570, respectively).
Tripathy. SABCS 2020. Abstr PD2-04. Slide credit: clinicaloptions.com
 MONALEESA-7: Updated OS in ITT Population
(Key Secondary Endpoint)
 24% relative reduction in risk of
100 +++++++++ ++
++++ + +++ + death with addition of
+ + +++
++ +
++ ++
ribociclib to ET
80 + +++ +
+++ +
++ + ++ +
+  Subgroup analyses, including by
+++ +
60 ++
+ ++++++
+++++ endocrine partner, generally
+++ +++++ ++++++++++++++++++++++++++++++
OS (%)

+++++++
++++++ ++++++++ ++
consistent with ITT population
+++++
40 RIB + ET PBO + ET +++++++++++++++++++ ++
Events/n 141/335 167/337 ‒ Median OS with NSAI:
Median OS, mos 58.7 48.0
58.7 mos with ribociclib vs
20
HR (95% CI) 0.763 (0.608-0.956)
47.7 mos with placebo (HR:
0.80; 95% CI: 0.62-1.04)
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66
‒ Median OS with tamoxifen:
Patients at
Mos NR with ribociclib vs 49.3 mos
Risk, n
Ribociclib 335 330 325 320 316 309 304 292 287 279 274 267 259 250 242 235 226 220 210 203 196 191 187 178 155 118 91 66 42 27
Placebo 337 330 325 321 315 311 303 297 290 283 275 262 255 237 223 212 210 199 192 180 175 165 157 146 122 90 63 46 29 17
8
5
2
3
1
0
0
0
with placebo (HR: 0.71; 95%
CI: 0.45-1.10)
Tripathy. SABCS 2020. Abstr PD2-04. Reproduced with permission. Slide credit: clinicaloptions.com
 MONALEESA Biomarker Analysis: Intrinsic BC Subtype
and Efficacy With Ribociclib + ET in HR+/HER2- Adv BC
 Phase III MONALEESA-2, -3, and -7 trials Ribociclib + ET Placebo + ET
Tumor Samples, n
demonstrated significant benefit with (n = 672) (n = 488)
ribociclib + ET vs placebo + ET in patients MONALEESA-2 180 178
with HR+/HER2- advanced BC MONALEESA-3 329 160
MONALEESA-7 163 150
 Current retrospective, exploratory
analysis evaluated association of intrinsic
BC subtype with efficacy benefit in 1160
pooled samples across MONALEESA trials
‒ 1303 tumor samples underwent gene
expression profiling, PAM50-based
subtyping, with 1160 passing QC
‒ Prognostic relationships evaluated by
univariate and multivariable Cox
proportion hazard models
Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com
 MONALEESA Biomarker Analysis:
Selected Baseline Characteristics
ITT Biomarker Population
Characteristic, n (%)
Placebo (n = 913) Ribociclib (n = 1153) Placebo (n = 488) Ribociclib (n = 672)

Histological grade
 Well differentiated 91 (10.0) 103 (8.9) 52 (10.7) 58 (8.6)
 Moderately differentiated 396 (43.4) 533 (46.2) 213 (43.6) 323 (48.1)
 Poorly or undifferentiated 233 (25.5) 270 (23.4) 131 (26.8) 166 (24.7)
 Missing/unknown 193 (21.1) 247 (21.4) 92 (18.9) 125 (18.6)

ECOG PS*
0 615 (67.4) 760 (65.9) 332 (68.0) 445 (66.2)
 +1 294 (32.2) 389 (33.7) 155 (31.8) 225 (33.5)

De novo metastatic disease*

 Yes 289 (31.7) 347 (30.1) 156 (32.0) 212 (31.5)
 No 623 (68.2) 806 (69.9) 332 (68.0) 460 (68.5)

Liver or lung metastases*

 Yes 482 (52.8) 597 (51.8) 259 (53.1) 364 (54.2)
 No 430 (47.1) 556 (48.2) 229 (46.9) 308 (45.8)

*Patients with missing values are not show (≤ 0.4% per subgroup).
Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com
 MONALEESA Biomarker Analysis:
Intrinsic Subtype Distribution Across Studies
MONALEESA-2 MONALEESA-3 MONALEESA-7 Pooled
Intrinsic Subtype, % (n = 358) (n = 489) (n = 313) (N = 1160)
Luminal A 50 49 40 47
Luminal B 29 20 25 24
HER2 enriched 8 15 15 13
Basal like 3 1 5 3
Normal like 11 15 15 14

 Intrinsic subtype distribution similar across all MONALEESA studies

Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com

 MONALEESA Biomarker Analysis:
PFS by Intrinsic Subtype
Placebo Ribociclib
Intrinsic P
Subtype Events, Median PFS, HR Valu
n Median PFS,
n Mos (95% CI) n Events, n e
Mos (95% CI)
Luminal A 222 110 19.48 (15.61-24.80)
Luminal B 124 89 12.85 (10.84-14.82) 0.6 < .00
320 114 29.60 (23.03-NR) 3 1
HER2E 52 41 5.52 (3.12-9.17)
0.5 < .00
Basal like 14 8 3.58 (1.87-NR) 154 66 22.21 (18.79-NR) 2 1
95 56 16.39 (12.71-24.6) 0.3 < .00
9 1
 A PFS benefit with ribociclib vs placebo
16 was
14 observed for all intrinsic
3.71 (1.91-13.0) .7672 1.1
5
subtypes except for basal like, which had the worst prognosis in both
treatment arms
 There was a statistically significant interaction between intrinsic
subtype and treatment arm (P = .045)
Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com
 MONALEESA Biomarker Analysis:
Multivariable Analysis of PFS Risk by Intrinsic Subtype
Ribociclib Placebo All Patients
Intrinsic Subtype, % Adjusted Adjusted Adjusted
P Value P Value P Value
PFS HR* PFS HR* PFS HR*
Luminal A 1.00 -- 1.00 -- 1.00 --
Luminal B 1.17 0.35 1.68 .00055 1.41 .0015
HER2 enriched 1.76 .00082 3.47 < .0001 2.30 < .0001
Basal like 5.1 < .0001 3.05 .0040 3.97 < .0001
Normal like 0.98 .93 1.69 .0028 1.31 .039
Ribociclib vs placebo -- -- -- -- 0.50 < .0001
*Multivariate Cox model adjusted for age, prior CT, prior ET, ECOG PS, visceral disease (liver or lung metastases), bone metastases, histology,
number of metastatic sites, de novo metastatic disease. Reference = luminal A subtype.

Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com

 Update on CDK4/6 Inhibition With Ribociclib in
HR+/HER2- MBC: Summary
 In an updated analysis of MONALEESA-7 with 53.5 mos of f/u, ribociclib + ET
continued to show an OS benefit in pre- or perimenopausal patients with
HR+/HER2- advanced BC vs ET alone[1]
‒ Median OS: 58.7 vs 48.0 mos, respectively (HR: 0.763; 95% CI: 0.608-0.956)
‒ OS benefit seen despite crossover and subsequent CDK4/6i use in placebo arm
and was generally consistent across subgroups, including ET partner
 In a correlative biomarker analysis across the phase III MONALEESA trials
evaluating ribociclib + ET vs ET alone for HR+/HER2- advanced BC, patients
with HER2E, luminal A or luminal B subtypes exhibited a consistent PFS
benefit with ribociclib treatment, whereas patients with basal-like subtype
did not[2]
1. Tripathy. SABCS 2020. Abstr PD2-04. 2. Prat. SABCS 2020. Abstr GS1-04. Slide credit: clinicaloptions.com
Update on PIK3 Inhibition With Alpelisib
in HR+/HER2- MBC
 BYLieve (Cohort B): Alpelisib + Letrozole in PIK3CA-
Mutated HR+/HER2- Advanced BC After CDK4/6i + AI
 International, open-label, multicohort, noncomparative phase II study
Cohort A: Prior CDK4/6i + AI
Alpelisib 300 mg PO QD +
Fulvestrant 500 mg IM†‡ *Centrally confirmed.
Men and pre/postmenopausal †
Fulvestrant given
women with PIK3CA-mutant* (minimum n = 112)
on Days 1 and 15 of cycle 1,
HR+/HER2- advanced BC; Cohort B: Prior CDK4/6i + FULV Day 1 for subsequent cycles.
immediate prior treatment with Alpelisib 300 mg PO QD + Current ‡
Men in letrozole cohort and
CDK4/6i + ET, systemic CT, or ET; no Letrozole 2.5 mg PO QD‡ analysis premenopausal women
prior PI3Ki; measurable disease or (n = 126) received goserelin 3.6 mg SC
≥ 1 predominantly lytic bone Q28D or leuprolide
Cohort C: Prior AI then CT or ET 7.5 mg IM Q28D for adequate
lesion; ECOG PS ≤ 2 Alpelisib 300 mg PO QD + gonadal suppression.
(estimated N = 390) Fulvestrant 500 mg IM†‡
(minimum n = 112)

 Primary endpoint: proportion of each cohort  Secondary endpoints (in each cohort):
alive without PD at 6 mos (RECIST v1.1) PFS, PFS2, ORR, CBR, DoR, OS, safety
‒ Endpoint met if lower 95% CI > 30%
Rugo. SABCS 2020. Abstr PD2-07. NCT03056755. Slide credit: clinicaloptions.com
 BYLieve (Cohort B): Baseline Characteristics
Prior CDK4/6i + FULV Prior CDK4/6i + FULV
Characteristic (n = 126) Characteristic, n (%) (n = 126)
Female, n (%) 126 (100) No. prior lines of tx in metastatic setting
Median age, yrs (range) 61.0 (37-80) 0 2 (1.6)†
1 66 (52.4)
Race, n (%) 2 56 (44.4)
 Asian 8 (63) 3 2 (1.6)
 Black 1 (0.8)
 White 85 (67.5) No. prior lines of ET in metastatic setting
 Other/unknown/missing 32 (25.4) 0 2 (1.6)†
1 73 (57.9)
ECOG PS 0/1/2,* n (%) 59 (46.8)/61 (48.4)/2 (1.6) 2 49 (38.9)
3 2 (1.6)
*Missing for 4 patients.
†
Received CK4/6i in adjuvant setting, n = 1; in palliative setting, n = 1.
Endocrine status at study entry‡
‡
Per ESMO definitions: primary endocrine resistance, relapse < 24 mos
on adjuvant ET or progression < 6 mos on first-line ET in metastatic
 Primary endocrine resistance 12 (9.5)
 Secondary endocrine resistance 73 (57.9)
setting; secondary endocrine resistance, relapse ≥ 24 mos on ET or
 Endocrine sensitivity 5 (4.0)
relapse < 12 mos after end of adjuvant ET or progression ≥ 6 mos on ET
in metastatic setting; endocrine sensitivity, relapse ≥ 12 mos after end Progressed on prior AI 103 (81.7)
of adjuvant ET or progression ≥ 12 mos after end of ET in metastatic
setting.
Rugo. SABCS 2020. Abstr PD2-07. Slide credit: clinicaloptions.com
 BYLieve (Cohort B): Efficacy
 Primary endpoint met in modified full mFAS* With
analysis set* of cohort B patients who Investigator-Assessed mFAS* Measurable
Outcome, n (%) (n = 115) Disease
received prior CDK4/6i + FULV (n = 101)

‒ 53/115 (46.1%) alive without PD at Best overall response

6 mos per investigator assessment  CR 0 0
 PR 18 (15.7) 18 (17.8)
‒ Lower bound of 95% CI > 30%  Neither CR nor PR 8 (7.0) 0
 SD 49 (42.6) 49 (48.5)
 PD 20 (17.4) 19 (18.8)
 Median PFS in mFAS*: 5.7 mos  Unknown 20 (17.4) 15 (14.9)

 Reduction in tumor size (66.3%) ORR 18 (15.7) 18 (17.8)

comparable to cohort A patients who
received alpelisib + FULV after PD on
prior CDK4/6i + AI (70.1%)
Rugo. SABCS 2020. Abstr PD2-07.
Clinical benefit rate† 37 (32.2) 32 (31.7)
*Patients with centrally confirmed PIK3CA mutation.
†
Clinical benefit rate = CR + PR + SD + non-CR/non-PD ≥ 24 wks.
Slide credit: clinicaloptions.com
 BYLieve (Cohort B): Safety
Prior CDK4/6i + FULV (n = 126) Prior CDK4/6i + FULV (n = 126)
AE, n (%) AE in ≥ 20% of Patients, n (%)
All Grades Grade ≥ 3 All Grades Grade ≥ 3
AE 126 (100) 88 (69.8) Diarrhea 85 (67.5) 5 (4.0)
TRAE 126 (100) 72 (57.1) Hyperglycemia 80 (63.5) 32 (25.4)
Serious AE 45 (35.7) 38 (30.2) Nausea 69 (54.8) 3 (2.4)
Serious TRAE 17 (13.5) 17 (13.5) Rash 39 (31.0) 12 (9.5)
AE leading to d/c* 18 (14.3) 11 (8.7) Rash maculopapular 21 (16.7) 10 (7.9)
TRAE leading to d/c* 16 (12.7) 9 (7.1) Fatigue 39 (31.0) 5 (4.0)
AE leading to dose Decreased appetite 56 (44.4) 1 (0.8)
91 (72.2) 69 (54.8)
adjustment/interruption
Stomatitis 43 (34.1) 1 (0.8)
*Patients could have ≥ 1 AE leading to d/c. Vomiting 31 (24.6) 1 (0.8)
 2 fatal serious AEs (cerebral ischemia, septic shock) Asthenia 27 (21.4) 5 (4.0)

 Most common reasons for dose adjustment/  No differences observed in frequency and grade of
interruption: hyperglycemia (28.6%), diarrhea rash for patients who did vs did not receive
(10.3%), rash (10.3%) prophylactic antihistamines

Rugo. SABCS 2020. Abstr PD2-07. Slide credit: clinicaloptions.com

 SOLAR-1: Alpelisib + Fulvestrant vs Placebo +
Fulvestrant in HR+/HER2- Advanced Breast Cancer
 Randomized, double-blind, placebo-controlled phase III trial
Stratification by presence of liver/lung mets, prior CDK4/6i therapy
Alpelisib 300 mg QD PO + Fulvestrant 500 mg IM†
Men or postmenopausal PIK3CA- (n = 169)
mutant Significantly improved ORR
women with HR+/HER2-
cohort* (26.6% vs 12.8%) and
advanced BC with Placebo QD PO + Fulvestrant 500 mg IM†
(n = 341) PFS (11.0 vs 5.7 mos;
recurrence or progression (n = 172)
HR: 0.65; P < .001) with
on/after prior AI,
alpelisib vs placebo
measurable disease or Alpelisib 300 mg QD PO + Fulvestrant 500 mg IM†
PIK3CA- in patients with
≥ 1 predominantly lytic (n = 115)
nonmutant PIK3CA-mutated
bone lesion, ECOG PS 0/1
cohort advanced BC
(N = 572) Placebo QD PO + Fulvestrant 500 mg IM†
(n = 231) (n = 116)
*Prospective mutation testing performed using PCR-based assays, which identified mutations in exons 7, 9, and 20 (C420R,
E542K, E545A/D/G/K, Q546E/R, H1047L/R/Y). †Fulvestrant given on Days 1,15 of 28 in cycle 1, then Day 1 thereafter.
 Primary endpoint: PFS (locally assessed) in all patients randomized to PIK3CA-mutant cohort
 Secondary endpoints: OS in PIK3CA-mutant cohort; PFS in PIK3CA-nonmutant cohort (proof of
concept); PFS in ctDNA and ORR/CBR for both cohorts; safety for patients with ≥ 1 dose study drug
Ciruelos. SABCS 2020. Abstr PD2-06. André. NEJM. 2019;380:1929. NCT02437318. Slide credit: clinicaloptions.com
 SOLAR-1 Biomarker Analysis: Methods
 Current exploratory analysis of SOLAR-1  381 (67%) of patients across SOLAR-1
evaluated outcomes in patients with had valid ctDNA data at BL, with 193
and without PIK3CA alterations as (51%) of these patients harboring a
retrospectively detected in ctDNA by PIK3CA alteration
NGS
PIK3CA Alterations in ctDNA at BL Patients
‒ NGS identified alterations not by NGS, n (%) (n = 193)
detectable by PCR tests used during No. alterations
study screening  Single 147 (76)
 Multiple 46 (24)
‒ For NGS testing, PIK3CA alterations Detectable by PCR 168 (87)
defined as single/multiple genetic
Exon 7 alteration 11 (6)
changes that may or may not lead to
amino acid changes or copy number Exon 9 alteration 70 (36)
variation (amplification) Exon 20 alteration 102 (53)

Ciruelos. SABCS 2020. Abstr PD2-06. Slide credit: clinicaloptions.com

 SOLAR-1 Biomarker Analysis: Discordance Between
PIK3CA Detection in ctDNA vs Tumor Tissue
PFS by Tumor Tissue PIK3CA Alteration Status
 38% (72/188) of patients in Patients Without PIK3CA Alteration(s) in ctDNA by NGS
deemed PIK3CA nonaltered in 1.0

plasma ctDNA by NGS found to

PFS Probability
0.75
have PIK3CA alterations in tissue
0.50
by NGS and/or PCR
0.25
‒ These patients had prolonged
PFS with alpelisib + FULV vs 0
0 4 8 12 16 20 24 28
Mos
those confirmed to be PIK3CA Patients at Risk, n
55 19 9 2 2 0 0 0
non-altered in tumor tissue 43
19
18
12
8
8
2
8
0
4
0
2
0
0
0
0
20 16 9 9 6 3 2 1
 Suggests that reflex PIK3CA Group Events n mPFS (95% CI) HR (95% CI)

testing of tumor tissue should Placebo + fulvestrant/PIK3CA non-altered 31 55 5.1 (3.7-9.0) 0.69
(0.38- 1.27)
be done when no PIK3CA Alpelisib + fulvestrant/PIK3CA non-altered 18 43 9.2 (3.8-NA)
Placebo + fulvestrant/PIK3CA altered 11 19 10.1 (3.6-NA)
alteration is detected in ctDNA Alpelisib + fulvestrant/PIK3CA altered 8 20 22.1 (5.5-NA)
0.54
(0.19-1.50)

Ciruelos. SABCS 2020. Abstr PD2-06. Reproduced with permission. Slide credit: clinicaloptions.com
 Update on PIK3 Inhibition With Alpelisib in
HR+/HER2- MBC: Summary
 BYlieve: In an analysis of Cohort B examining alpelisib + letrozole in PIK3CA-
mutated HR+/HER2- advanced BC after CDK4/6i + fulvestrant, the primary endpoint
was met, with 46.1% of patients alive at 6 mos without progression[1]
‒ Median PFS: 5.7 mos
 SOLAR-1: Exploratory biomarker analysis found a clinical benefit with alpelisib +
fulvestrant regardless of source of material (ctDNA or tissue FFPE) used to assess
PIK3CA alterations using NGS[2]
‒ The clinical benefit was consistent with PIK3CA mutations detected in tumor tissue by
NGS and PCR
‒ There was discordance between PIK3CA mutations detected by ctDNA vs tumor tissue
‒ Investigators suggest reflex testing with tissue samples when no PIK3CA alterations detected
by ctDNA
1. Rugo. SABCS 2020. Abstr PD2-07. 2. Ciruelos. SABCS 2020. Abstr PD2-06. Slide credit: clinicaloptions.com
Advances in HER2+ MBC
Update on HER2 TKIs in HER2+ MBC
 NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC
With ≥ 2 Prior Lines of HER2-Targeted Therapy
 International, open-label, randomized phase III trial
21-day cycle
Stratified by no. prior HER2-targeted therapies, disease
location, hormone receptor status, geographic location

Neratinib 240 mg/day PO continuously +

Patients with centrally confirmed
Capecitabine* 1500 mg/m2 PO on Days 1-14†
HER2+ MBC; previously treated Until PD
(n = 307)
with ≥ 2 lines of HER2-targeted
agents for MBC; asymptomatic, Survival
Lapatinib 1250 mg/day PO continuously +
stable brain metastases allowed follow-up
Capecitabine* 2000 mg/m2 PO on Days 1-14
(N = 621)
(n = 314)
*BID in 2 evenly divided doses. †Loperamide administered at 4 mg with first neratinib dose followed by 2 mg Q4H
for first 3 days, followed by 2 mg every 6-8 hrs through end of cycle 1; as needed thereafter. No ET permitted.

 Coprimary endpoints: OS, PFS (centrally  Secondary endpoints: PFS (locally

confirmed) determined), ORR, DoR, CBR, time to
intervention for CNS mets, safety, PRO
‒ Study positive if either endpoint statistically
significant (OS, P < .04; PFS, P < .01)
Saura. JCO. 2020;38:3138. Saura. SABCS 2020. Abstr PD13-09. Slide credit: clinicaloptions.com
 NALA: Analysis of Patients With Baseline CNS Disease
 Of 621 randomized patients, 101 (16.3%) had asymptomatic CNS mets at BL
‒ BL characteristics generally well balanced between arms, similar to ITT population
Screened for eligibility
(n = 1015)
Enrollment

Ineligible Patients w/
(n = 394) Characteristic CNS Mets at BL
Randomly assigned
(n = 621)
(n = 101)
Mean age, yrs (range) 54 (25-75)
Allocation

Neratinib + capecitabine Lapatinib + capecitabine ECOG PS 1, n (%) 58 (57.4)

(n = 307) (n = 314)
HR+ disease, n (%) 51 (50.5)
Brain not indicated Brain indicated as Brain not indicated Brain indicated as
as disease location disease location at as disease location disease location
Prior CNS-directed local 81 (80.2)
at enrollment enrollment at enrollment at enrollment therapy, n (%)
CNS Analysis

(n = 256) (n = 51) (n = 264) (n = 50)

50 received and 49 received and Prior corticosteroids, n (%) 21 (20.8)
1 did not receive 1 did not receive
study treatment study treatment Prior anti-epileptics, n (%) 10 (9.9)

Saura. SABCS 2020. Abstr PD13-09. Slide credit: clinicaloptions.com

 NALA: Efficacy in Patients With Baseline CNS Disease
Efficacy Outcome Neratinib + Cape (n = 51) Lapatinib + Cape (n = 50)
Restricted mean PFS*, mos 7.8 5.5
HR (95% CI) 0.66 (0.41-1.05; P = .074)
Restricted mean OS*, mos 16.4 15.4
HR (95% CI) 0.90 (0.59-1.38; P = .635)
Time to intervention for CNS disease
 12-mo cumulative incidence, % 25.5 36.0
 P value .430
Median CNS PFS, mos 12.4 8.3
HR (95% CI) 0.62 (0.32-1.18; P = .143)
*Prespecified restriction of 24 mos for PFS and 48 mos for OS. Data cutoff: September 28, 2018.
Median duration of study tx: neratinib, 5.7 mos (range: 0.4-28.6); lapatinib, 3.5 mos (range: 0.5-20.8).

 Among 3 patients with LMD: n = 2 in neratinib arm had PD after 5.6 and 9.8 mos with an OS of 17.4
and 19.8 mos, respectively; n = 1 in lapatinib arm had PD after 4.3 mos with an OS of 6.5 mos
Saura. SABCS 2020. Abstr PD13-09. Slide credit: clinicaloptions.com
 NALA: HRQoL with Neratinib in Patients with HER2+
MBC and ≥ 2 Prior Lines of HER2-Targeted Therapy
 Mean EORTC QLQ-C30 summary scores and Global Health Status subscale scores
remained stable over time in both treatment arms
 No difference between the 2 arms in TTD of QLQ-C30 summary scores (HR: 0.94;
95% CI: 0.63-1.40; P = .7560) or Global Health Status subscale scores (HR: 0.89; 95%
CI: 0.63-1.25; P = .4982)
 Mean scores for QLQ-C30 physical functioning maintained near BL values in both
arms over time, with transient increase from BL to cycle 3 in mean diarrhea
subscale scores that abated gradually
 No difference in TTD of physical functioning, fatigue, or constipation scales between
the 2 arms
‒ TTD for diarrhea scale was shorter in neratinib arm vs lapatinib arm (median TTD: 3.5 vs
20.9 mos; HR: 1.709; 95% CI: 1.318-2.226; P < .0001)
Moy. SABCS 2020. Abstr PS9-02. Slide credit: clinicaloptions.com
 HER2CLIMB: Tucatinib or Placebo + Trastuzumab/
Capecitabine in Previously Treated HER2+ MBC
 Randomized, double-blind, placebo-controlled, active comparator phase II trial at 155 sites in
15 countries
Stratified by brain mets (yes vs no), ECOG PS (0 vs 1), 21-day cycles
and region (US or Canada vs rest of world)

Tucatinib 300 mg PO BID +

Patients with HER2+ MBC; Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) +
prior trastuzumab, pertuzumab, Capecitabine 1000 mg/m2 PO BID on Days 1-14
and T-DM1; ECOG PS 0/1; (n = 410)
brain mets allowed*
(N = 612) Placebo PO BID +
*All patients had baseline brain MRI. Included previously Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) +
treated stable mets, untreated mets not needing immediate Capecitabine 1000 mg/m2 PO BID on Days 1-14
local therapy, and previously treated progressing mets not (n = 202)
needing immediate local therapy.

 Primary endpoint: PFS (RECIST v 1.1 by BICR)
among first 480 randomized patients
‒ 90% power with 288 events at α = 5%, HR: 0.67
Murthy. NEJM. 2020;382:597. Hamilton. SABCS 2020. Abstr PD3-08. NCT02614794.
 Secondary endpoints (total population):
OS, PFS in patients with brain mets, ORR in
patients with measurable disease, safety in
patients who received ≥ 1 dose of study tx
Slide credit: clinicaloptions.com
 HER2CLIMB: Response by HR Status
With Measurable Disease (n = 511)
Confirmed Response per HR+ Subgroup HR- Subgroup
BICR (RECIST v1.1) Tucatinib Arm Pbo Arm Tucatinib Arm Pbo Arm
(n = 203) (n = 107) (n = 137) (n = 64)
ORR, % 37.4† 27.1† 45.3‡ 15.6‡
Best overall response, n (%)
 CR 1 (0.5) 2 (1.9) 2 (1.5) 0
 PR 75 (36.9) 27 (25.2) 60 (43.8) 10 (15.6)
 SD 99 (48.8) 60 (56.1) 56 (40.9) 40 (62.5)
 PD 16 (7.9) 13 (12.1) 11 (8.0) 11 (17.2)
 Not evaluable 0 0 0 1 (1.6)
 Not available* 12 (5.9) 5 (4.7) 8 (5.8) 2 (3.1)

*Response not assessed post baseline. †P = .07. ‡P = .00008.

Hamilton. SABCS 2020. Abstr PD3-08. Slide credit: clinicaloptions.com

 HER2CLIMB: Survival by HR Status
Primary Endpoint (PFS) or Total Study (OS) Population With Baseline Brain Metastases
Outcome by HR+ Subgroup HR- Subgroup HR+ Subgroup HR- Subgroup
HR Status
Tucatinib Placebo Tucatinib Placebo Tucatinib Placebo Tucatinib Placebo
Arm Arm Arm Arm Arm Arm Arm Arm
PFS (per BICR)
Events, n/N 106/190 66/99 72/130 31/61 56/107 36/59 50/91 15/34
1-yr rate, % 31.3 11.3 35.4 15.8 23.8 0 26.0 0
Median, mos 7.6 5.6 8.1 4.2 7.5 5.1 7.8 5.4
Hazard ratio 0.58 (0.42-0.80) 0.54 (0.34-0.86) 0.48 (0.31-0.75) 0.50 (0.27-0.95)
(95% CI) P = .0008 P = .008 P = .0008 P = .03
OS
Events, n/N 78/243 51/127 52/167 35/75 36/107 28/59 32/91 18/34
2-yr rate, % 40.2 30.7 51.3 17.3 37.5 0 44.1 0
Median, mos 21.7 18.2 31.1 14.1 18.1 12.8 18.5 11.5
Hazard ratio 0.85 (0.59-1.23) 0.50 (0.31-0.80) 0.76 (0.46-1.26) 0.37 (0.19-0.70)
(95% CI) P = .4 P = .003 P = .3 P = .001

Hamilton. SABCS 2020. Abstr PD3-08. Slide credit: clinicaloptions.com

 HER2CLIMB: HRQoL in Patients With Brain Metastases
 HRQoL assessed in n = 164 patients with brain metastases at BL; cycles 3, 5, 7, and
9; and at 30-day follow-up (tucatinib arm, n = 107; placebo arm, n = 57)
 HRQoL per EQ-5D-5L Health Score maintained throughout treatment with no
marked differences between arms
 Tucatinib arm showed significantly prolonged time to worsening of HRQoL
EQ-5D-5L Health Score vs placebo arm
‒ 49% reduction in risk of deterioration (HR: 0.51; 95% CI: 0.28-0.93)
 No evident change in EQ-5D-5L subscale responses from BL through treatment
‒ However, at 30-day follow up after discontinuing treatment, worsening observed for
mobility, usual activities, pain/discomfort, and self-care

Wardley. SABCS 2020. Abstr PD13-04. Slide credit: clinicaloptions.com

 HER2CLIMB-02: Tucatinib or Placebo + T-DM1 in
Previously Treated HER2+ Advanced BC
 Randomized, international, double-blind phase III trial
Stratified by line of treatment for metastatic disease, HR status,
presence/history of brain mets, and ECOG PS status

Adults with unresectable locally

advanced or metastatic HER2+ BC; Tucatinib 300 mg PO BID +
PD after trastuzumab and T-DM1 3.6 mg/kg Q21D Until PD,
taxane in any setting; unacceptable toxicity,
no prior anti-HER2, anti-EGFR, or withdrawal of consent,
HER2 TKI; prior pertuzumab Placebo PO BID + or study closure
allowed; ECOG PS 0/1; T-DM1 3.6 mg/kg Q21D
stable brain mets allowed
(planned N = 460) Assessed for PD Q6W for first 24 wks, then Q9W thereafter.

 Primary endpoint: investigator-assessed PFS (RECIST v 1.1)

 Key secondary endpoints: OS, investigator-assessed ORR (RECIST v 1.1)
Hurvitz. SABCS 2020. Abstr OT-28-01. NCT03975647. Slide credit: clinicaloptions.com
 Update on HER2 TKIs in HER2+ MBC: Summary
 NALA: Subgroup analysis of patients with HER2+ MBC and CNS mets suggested an association between
improved PFS and CNS outcomes with neratinib + capecitabine [1]
‒ Restricted mean PFS: 7.8 vs 5.5 mos with lapatinib/capecitabine (hazard ratio: 0.66)

‒ Median CNS PFS: 12.4 vs 8.3 mos with lapatinib/capecitabine (hazard ratio : 0.626)

‒ 2 patients with LMD treated with neratinib had PD at 5.6 and 9.8 mos

‒ Patient HRQoL and physical functioning maintained in both treatment arms [2]

 HER2CLIMB: Exploratory analysis of efficacy outcomes by HR status found consistent OS benefit with the
addition of tucatinib to trastuzumab + capecitabine in both HR+ and HR- subgroups (hazard ratio: 0.85 and
0.50, respectively)[3]
‒ Clinically meaningful improvements in PFS regardless of HR status or presence of brain mets [3]

‒ Tucatinib arm showed significantly prolonged time to worsening of HRQoL [4]

‒ Phase III HER2CLIMB-02 trial evaluating tucatinib or placebo + T-DM1 in previously-treated HER2+ advanced BC [5]
1. Saura. SABCS 2020. Abstr PD13-09. 2. Moy. SABCS 2020. Abstr PS9-02. 3. Hamilton. SABCS 2020. Abstr PD3-08.
4. Wardley. SABCS 2020. Abstr PD13-04. 5. Hurvitz. SABCS 2020. Abstr OT-28-01. Slide credit: clinicaloptions.com
Advances in the Treatment of
HER2-Mutant, HR+ MBC
 SUMMIT: Neratinib + Trastuzumab + Fulvestrant in
HER2-Mutant, HR+ MBC
 International, open-label, multicohort phase II study
‒ Current analysis concerns cohort with HER2-mutant, HR+ MBC

Patients with
HER2-mutant,* HR+ MBC;
Neratinib +
histologically confirmed and
Trastuzumab + Fulvestrant
RECIST v1.1 evaluable disease;
(n = 51)
with or without prior CDK4/6i;
ECOG PS ≤ 2
*Documented EGFR exon 18 or HER2 mutation by local genomic sequencing.

 Primary endpoint: ORR at first tumor assessment

 Secondary endpoints: ORR (confirmed), CBR, PFS, DoR, safety, biomarkers
Jhaveri. SABCS 2020. Abstr PD1-05. NCT01953926. Slide credit: clinicaloptions.com
 SUMMIT: Prior Therapy and Patient Disposition
Parameter Safety Evaluable Patients (n = 51)
Prior therapies for locally advanced and metastatic disease, n (%) 46 (90.2)
Median number of prior therapies (range) 4 (1-10)
Prior endocrine therapy n (%)
 Aromatase inhibitor 35 (68.6)
 Fulvestrant 36 (70.6)
 Tamoxifen 4 (7.8)
Other prior therapy, n (%)
 Chemotherapy 35 (68.6)
 Anti-HER2 therapy 2 (3.9)
 CDK4/6 inhibitor 30 (58.8)
 PIK3CA inhibitor 4 (7.9)
 mTOR inhibitor 15 (29.4)
Median duration of treatment, mos (range) 6.7 (0.9-31.6)
Patients continuing on treatment, n (%) 18 (35.3)

Jhaveri. SABCS 2020. Abstr PD1-05. Slide credit: clinicaloptions.com

 SUMMIT: Efficacy Summary
DoR and Best Response (n = 37*)
L755S & V697L
Y772_A775dup‡ Patients
L755S Outcome
V777L (n = 37*)
S310F & V777L
G778_P780dup
Y772_A775dup
G778_P780dup ORR, n (%) 17 (45.9)
S310Y CR
V777L  CR 1 (2.7)
L755S
D769Y
PR  PR 16 (43.2)
G776V SD
L755S
L755S PD
Mutation Status

V777L
Time of First Response
Best ORR, n (%) 21 (56.8)
L755S & S310Y
S310F
Treatment Ongoing
 CR 1 (2.7)
D769H
deltaLRE  PR 20 (54.1)
L755P
L755S
L755S
G778_P780dup Median DoR, mos (95% CI) 10.9 (6.4-NE)
D769Y
V777L
L755S CBR, n (%) 20 (54.1)
S310F
L755S *Patients evaluable by RECIST.  CR or PR 17 (45.9)
V777L
L755S †
Missed tumor assessment prior to  SD ≥ 24 wks 3 (8.1)
S310F
G778_P780dup patient death in hospice due to PD.
V777L Median PFS, mos (95% CI) 8.3 (4.2-14.5)
V777L†
L755S
‡
First PR at Wk 18, first CR at Wk 63.
L755S
0 9 18 27 36 45 54 63 72 81 90 99 108 117 126 135 144
Duration of Treatment (Wks)
Jhaveri. SABCS 2020. Abstr PD1-05. Reproduced with permission. Data cutoff: October 16, 2020. Slide credit: clinicaloptions.com
 SUMMIT: Treatment-Emergent AEs
Safety Evaluable Patients Safety Evaluable
TEAEs, n (%) (n = 51) Diarrhea Characteristics Patients
(n = 51)
All Grades Grade 3/4
Patients with ≥ 1 AE 49 (96.1) 33 (64.7) Incidence of diarrhea, n (%)
 Any grade 45 (88.2)
Diarrhea 45 (88.2) 20 (39.2)*  Grade 1 13 (25.5)
Nausea 34 (66.7) 0  Grade 2 12 (23.5)
 Grade 3 20 (39.2)
Constipation 21 (41.2) 0
Fatigue 18 (35.3) 3 (5.9) Action taken with neratinib, n (%)
 Temporary hold 21 (41.2)
Vomiting 22 (43.1) 2 (3.9)  Dose reduction 11 (21.6)
Decreased appetite 20 (39.2) 3 (5.9)  Permanent d/c 0
 Hospitalization 1 (2.0)
Abdominal pain 12 (23.5) 0
Headache 8 (15.7) 0 Median cumulative duration of
6 (1-16.5)
grade 3 diarrhea/patient, days (IQR)
*No patient had grade 4 diarrhea.

Jhaveri. SABCS 2020. Abstr PD1-05. Slide credit: clinicaloptions.com

 Advances in the Treatment of HER2-Mutant, HR+ MBC:
Summary
 SUMMIT: In the latest analysis of the cohort of patients with heavily
pretreated HER2-mutant, HR+/HER2- MBC, neratinib + fulvestrant +
trastuzumab demonstrated clinical activity
‒ ORR: 45.9%; median DoR: 10.9 mos; median PFS: 8.3 mos
‒ Included patients who previously received fulvestrant and/or CDK4/6i
‒ Increased levels of grade 3 diarrhea were reported but manageable with
loperamide prophylaxis
‒ SUMMIT amended to include comparison of neratinib + fulvestrant +
trastuzumab vs fulvestrant alone, enrollment ongoing

Jhaveri. SABCS 2020. Abstr PD1-05. Slide credit: clinicaloptions.com

Advances in the Treatment of
Metastatic TNBC
 KEYNOTE-355: Study Design
 Randomized, double-blind, multicenter phase III trial
‒ Current analysis reports PFS by CT regimen and key secondary endpoints
Stratified by CT (taxane vs gemcitabine/carboplatin); PD-L1 tumor expression
(CPS > 1 vs < 1); previous Tx with same class of CT for EBC (yes vs no)

Adult patients with previously

Pembrolizumab 200 mg IV Q3W + CT*
untreated locally recurrent Until PD, toxicity, or
(n = 566)
inoperable or metastatic TNBC; completion of 35
completed curative intent cycles of
therapy ≥ 6 mos before first Placebo + CT* pembrolizumab/
recurrence; ECOG PS 0/1; (n = 281) placebo
no active CNS mets
(N = 847) *Investigator’s choice of CT was permitted: nab-paclitaxel 100 mg/m 2 IV on Days 1, 8, 15 of 28-day
cycle; paclitaxel 90 mg/m2 IV on Days 1, 8, 15 of 28-day cycle; or gemcitabine 1000 mg/m 2 +
carboplatin AUC 2 on Days 1, 8 of 21-day cycle

 Primary endpoints: PFS and OS (in PD-L1 CPS ≥ 10, PD-L1 CPS ≥ 1, and ITT)
 Secondary endpoints: ORR, DoR, DCR, safety
Rugo. SABCS 2020. Abstr GS3-01. Slide credit: clinicaloptions.com
 KEYNOTE-355: Baseline Characteristics (ITT)
Characteristics, n (%) Pembrolizumab + CT (n = 566) Placebo + CT (n = 281)
Age, median yrs (range) 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)
CT on study
 Nab-paclitaxel 173 (30.6) 95 (33.8)
 Paclitaxel 82 (14.5) 32 (11.4)
 Gemcitabine/carboplatin 311 (54.9) 154 (54.8)
Previous same-class CT
 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 mos 126 (22.3) 50 (17.8)
 ≥ 12 mos 270 (47.7) 147 (52.3)

Rugo. SABCS 2020. Abstr GS3-01. Slide credit: clinicaloptions.com

 KEYNOTE-355: PFS by Chemotherapy Regimen
Across Subgroups
PD-L1 CPS ≥ 10 PD-L1 CPS ≥ 1 ITT

mPFS, Mos mPFS, Mos mPFS, Mos

Pembro PBO + HR Pembro PBO + HR Pembro PBO + HR
Subgroup N + CT CT (95% CI) Subgroup N + CT CT (95% CI) Subgroup N + CT CT (95% CI)
0.65 0.74 0.82
Overall 323 9.7 5.6
(0.49-0.86) Overall 636 7.6 5.6 (0.61-0.90) Overall 847 7.5 5.6
(0.69-0.97)
On-Study CT On-Study CT On-Study CT
0.57 0.66 0.69
Nab-Pac 99 9.9 5.5 (0.34-0.95)
Nab-Pac 204 6.3 5.3
(0.47-0.92) Nab-Pac 268 7.5 5.4 (0.51-0.93)
0.33 0.46 0.57
Pac 44 9.6 3.6
(0.14-0.76)
Pac 84 9.4 3.8
(0.26-0.82)
Pac 114 8.0 3.8
(0.35-0.93)
0.77 0.86 0.93
Gem-Carbo 180 8.0 7.2 Gem-Carbo 348 7.5 7.5 Gem-Carbo 465 7.4 7.4
(0.74-1.16)
(0.53-1.11) (0.66-1.11)

0 0.5 1.0 1.5 0 0.5 1.0 1.5 0 0.5 1.0 1.5

HR (95% CI) HR (95% CI) HR (95% CI)
Favors Favors Favors Favors Favors Favors
Pembro + CT Placebo + CT Pembro + CT Placebo + CT Pembro + CT Placebo + CT

Rugo. SABCS 2020. Abstr GS3-01. Reproduced with permission. Slide credit: clinicaloptions.com
 KEYNOTE-355: ORR by Chemotherapy Regimen
Across Subgroups
PD-L1 CPS ≥ 10 PD-L1 CPS ≥ 1 ITT
70 63.6 70 70

60 54.0 53.2 60 54.8 60

50.0
44.6 43.8 45.2
50 39.8 50 43.1 43.5 50 45.1 42.2 41.0
ORR (%)

37.9 35.9
36.1 36.4 40.5 40.2
40 40 40
29.7 28.4
27.3 28.1
30 30 30

20 20 20

10 10 10

0 0 0
n = 99 n = 44 n = 180 n = 323 n = 204 n = 84 n = 348 n = 636 n = 268 n = 114 n = 465 n = 847
Nab-Pac Pac Gem-Carbo Overall Nab-Pac Pac Gem-Carbo Overall Nab-Pac Pac Gem-Carbo Overall

Pembrolizumab + CT Placebo + CT

Rugo. SABCS 2020. Abstr GS3-01. Reproduced with permission. Slide credit: clinicaloptions.com
 KEYNOTE-355: Duration of Response by Subgroup
PD-L1 CPS ≥ 10 PD-L1 CPS ≥ 1 ITT
mDoR, Mos (Range) mDoR, Mos (Range) mDoR, Mos (Range)
Pembro + CT 19.3 (1.6+ to 29.8) Pembro + CT 10.1 (1.0+ to 29.8) Pembro + CT 10.1 (1.0+ to 29.8)
PBO + CT 7.3 (1.5 to 32.5+) PBO + CT 6.5 (1.5 to 32.5+) PBO + CT 6.4 (1.5 to 32.5+)
82.8 100 76.9 100 78.0
100
58.5 57.9 54.9
% Remaining in Response

90 90 90
80 80 80
55.9 47.1 70 46.7
70 70 31.7
39.0 60
29.0 60
60
50 50 50
40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
0
3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33
Mos Mos Mos
Patients at Risk, n Patients at Risk, n Patients at Risk, n
117 107 84 62 49 43 35 24 12 7 0 0 192 173126 88 67 59 46 31 15 9 0 0 232 210 155106 82 66 53 31 15 9 0 0
41 38 22 16 14 12 7 6 5 3 1 0 80 72 39 26 19 16 10 7 5 3 1 0 101 91 46 33 25 20 12 9 6 4 1 0

Rugo. SABCS 2020. Abstr GS3-01. Reproduced with permission. Slide credit: clinicaloptions.com
 Advances in the Treatment of Metastatic TNBC:
Summary
 KEYNOTE-355: First-line pembrolizumab + CT improved PFS in a statistically
significant and clinically meaningful way alone in patients with PD-L1 positive
(CPS ≥ 10) metastatic TNBC[1]
‒ Median PFS: 9.7 vs 5.6 mos with CT alone (HR: 0.65; 95% CI: 0.49-0.86; P = .0012)
 PFS was improved with pembrolizumab treatment regardless of CT partner in ITT
population and across PD-L1 subgroups (CPS ≥ 10 and ≥ 1)[2]
 Secondary response outcomes also favored pembrolizumab + CT[2]
 Pembrolizumab in combination with chemotherapy has accelerated FDA approval
for the treatment of patients with locally recurrent unresectable or metastatic
TNBC whose tumors express PD-L1 (CPS ≥ 10)[3]

1. Cortes. ASCO 2020. Abstr 1000. 2. Rugo. SABCS 2020. Abstr GS3-01. 3. Pembrolizumab PI. Slide credit: clinicaloptions.com
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