Conference Highlights of SABCS 2018

CCO Conference Highlights of SABCS 2018
Supported by educational grants from Merck & Co., Inc. and
Novartis Pharmaceuticals Corporation.
2018 Annual Meeting of the CTRC-AACR San Antonio Breast
Cancer Symposium*
*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.

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Slide credit: clinicaloptions.com

Faculty
Mohammad Jahanzeb, MD, FACP
Professor of Clinical Medicine, Hematology-Oncology
Medical Director, UM Sylvester Deerfield Campus
Associate Center Director for Community Outreach
Sylvester Comprehensive Cancer Center
University of Miami, Miller School of Medicine
Deerfield Beach, Florida
Mohammad Jahanzeb, MD, FACP, has disclosed that he has received
consulting fees from Ipsen, Novartis, Pfizer, and Roche/Genentech and funds
for research support from Boehringer Ingelheim, Callisto, and Lilly.

KATHERINE: Trastuzumab Emtansine vs Trastuzumab
as Adjuvant Therapy for HER2+ EBC
 International, randomized, open-label phase III study
Patients with HER2+ EBC (cT1-4/N0-3/M0) who had
residual invasive disease in breast or axillary nodes
after neoadjuvant chemotherapy plus HER2-targeted
therapy* and surgery
(N = 1486)
T-DM1† 3.6 mg/kg IV Q3W x 14 cycles
(n = 743)
Trastuzumab 6 mg/kg IV Q3W x 14 cycles
(n = 743)
Slide credit: clinicaloptions.comGeyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].
Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum
of 9 wks taxane and trastuzumab. †Patients who d/c T-DM1 for toxicity allowed switch to trastuzumab to complete 14 cycles.
Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy,
pathological nodal status after neoadjuvant therapy
 Primary endpoint: IDFS
 Secondary endpoints including: distant recurrence-free survival, OS,
safety

KATHERINE: Baseline Characteristics
Characteristic
T-DM1
(n = 743)
Trastuzumab
(n = 743)
Median age, yrs (range)
 < 40 yrs, n (%)
 40-64 yrs, n (%)
 ≥ 65 yrs, n (%)
49 (24-79)
143 (19.2)
542 (72.9)
58 (7.8)
49 (23-80)
153 (20.6)
522 (70.3)
68 (9.2)
Race, n (%)
 White
 Asian
 American Indian*/Alaska native
 Black
 Other
551 (74.2)
65 (8.7)
36 (4.8)
21 (2.8)
70 (9.4)
531 (71.5)
64 (8.6)
50 (6.7)
19 (2.6)
79 (10.6)
Region, n (%)
 North America
 Western Europe
 Rest of world
170 (22.9)
403 (54.2)
170 (22.9)
164 (22.1)
403 (54.2)
176 (23.7)
Prior anthracycline, n (%) 579 (77.9) 564 (75.9)
Characteristic, n (%)
T-DM1
(n = 743)
Trastuzumab
(n = 743)
Primary tumor stage†‡
 ypT0, ypT1a, ypT1b, ypT1mic,
ypTis
 ypT1/ypT1c
 ypT2
 ypT3, ypT4
331 (44.5)
175 (23.6)
174 (23.4)
63 (8.5)
306 (41.2)
184 (24.8)
185 (24.9)
67 (9.0)
Regional lymph node stage†
 ypN0
 ypN1
 ypN2, ypN3
 ypNX
344 (46.3)
220 (29.6)
123 (16.6)
56 (7.5)
335 (45.1)
213 (28.7)
133 (17.9)
62 (8.3)
Residual invasive disease ≤ 1 cm
AND negative axillary nodes (ypT1a,
ypT1b, or ypT1mic and ypN0)
170 (22.9) 161 (21.7)
†At definitive surgery.
‡ypTX, n = 1 in trastuzumab arm; ypT1 without further subspecification, n = 5.
*Includes North, Central, and South American Indians.

KATHERINE: Stratification Factors
Stratification Factor, n (%) T-DM1 (n = 743) Trastuzumab (n = 743)
Clinical stage at presentation
 Operable (cT1-3N0–1M0)
 Inoperable (cT4NxM0 or cTxN2–3M0)
558 (75.1)
185 (24.9)
553 (74.4)
190 (25.6)
Hormone receptor status
 ER and/or PgR positive
 ER negative and PgR negative/unknown
534 (71.9)
209 (28.1)
540 (72.7)
203 (27.3)
Preoperative HER2-targeted therapy
 Trastuzumab alone
 Trastuzumab + other HER2-targeted agents*
•Trastuzumab + pertuzumab†
600 (80.8)
143 (19.2)
133 (17.9)
596 (80.2)
147 (19.8)
139 (18.7)
Pathologic nodal status after preoperative therapy
 Node positive
 Node negative/not done
343 (46.2)
400 (53.8)
346 (46.6)
397 (53.4)
*Includes afatinib, dacomitinib, lapatinib, neratinib, pertuzumab. †Not a stratification factor; for informational purposes only.

KATHERINE: IDFS
First IDFS
Event, %
T-DM1 T
Any 12.2 22.2
Distant
recurrence
10.5* 15.9†
Locoregional
recurrence
1.1 4.6
Contralateral
breast cancer
0.4 1.3
Death without
prior event
0.3 0.46 12
100
80
60
40
20
0
IDFS(%)
18 24 30 36 4842 54 600
Mos Since Randomization
707
676
681
635
658
594
633
555
561
501
409
342
142
119
255
220
44
38
4
4
743
743
Patients at Risk, n
T-DM1
Trastuzumab
Events, n (%)
3-yr IDFS, %
T-DM1
(n = 743)
91 (12.2)
88.3
Trastuzumab
(n = 743)
165 (22.2)
77.0
HR: 0.50 (95% CI: 0.39-0.64; P < .001)
CNS events: *5.9% vs †4.3%.

KATHERINE: IDFS by Subgroup
Subgroup
All patients
Age
< 40 yrs
40-64 yrs
≥ 65 yrs
Clinical stage at presentation
Inoperable breast cancer
Operable breast cancer
Hormone-receptor status
ER neg and PgR negative or unknown
ER and/or PgR positive
Preoperative HER2-directed therapy
Trastuzumab alone
Trastuzumab + other HER2-directed agents
Pathologic nodal status after preoperative therapy
Node positive
Node negative/not done
Primary tumor stage at definitive surgery
ypT0, ypT1a, ypT1b, ypT1mic, ypTis
ypT1, ypT1c
ypT2
ypT3
ypT4, ypTX
Regional lymph node stage at definitive surgery
ypN0
ypN1
ypN2
ypN3
ypNX
T-DM1 Better Trastuzumab Better
T-DM1
91/743
20/143
64/542
7/58
42/185
49/558
38/209
53/534
78/600
13/143
62/343
29/400
40/331
14/175
25/174
9/51
3/12
28/344
29/220
16/86
17/37
1/56
0.50 (0.39-0.64)
0.50 (0.29-0.86)
0.49 (0.36-0.67)
0.55 (0.22-1.34)
0.54 (0.37-0.80)
0.47 (0.33-0.66)
0.50 (0.33-0.74)
0.48 (0.35-0.67)
0.49 (0.37-0.65)
0.54 (0.27-1.06)
0.52 (0.38-0.71)
0.44 (0.28-0.68)
0.66 (0.44-1.00)
0.34 (0.19-0.62)
0.50 (0.31-0.82)
0.40 (0.18-0.88)
0.29 (0.07-1.17)
0.46 (0.30-0.73)
0.49 (0.31-0.78)
0.43 (0.24-0.77)
0.71 (0.35-1.42)
0.17 (0.02-1.38)
Trastuzumab
165/743
37/153
113/522
15/68
70/190
95/553
61/203
104/540
141/596
24/147
103/346
62/397
52/306
42/184
44/185
21/57
6/11
56/335
50/213
38/103
15/30
6/62
T-DM1
88.3
86.5
88.8
87.4
76.0
92.3
82.1
90.7
87.7
90.9
83.0
92.8
88.3
91.9
88.3
79.8
70.0
91.9
88.9
81.1
52.0
98.1
Events/Patients, n/N 3-Yr IDFS Rate, %HR (95% CI)
Trastuzumab
77.0
74.9
77.1
81.1
60.2
82.8
66.6
80.7
75.9
81.8
67.7
84.6
83.6
75.9
74.3
61.1
30.0
83.9
75.8
58.2
40.6
88.7
0.20 0.50 1.00 2.00 5.00

KATHERINE: Secondary Endpoints
6 12
100
80
60
40
20
0
FreedomFromDistant
Recurrence(%)
18 24 30 36 4842 54 600
707
679
682
643
661
609
636
577
564
520
412
359
143
126
254
233
45
41
4
4
743
743
Patients
at Risk, n
T-DM1
Trastuzumab
Events, n (%)
3-yr event-free rate, %
T-DM1
(n = 743)
78 (10.5)
89.7
Trastuzumab
(n = 743)
121 (16.3)
83.0
HR: 0.60 (95% CI: 0.45-0.79)
6 12
100
80
60
40
20
0
OS(%)
18 24 30 36 4842 54 600
719
695
702
677
693
657
668
635
648
608
508
471
195
175
345
312
76
71
12
8
743
743
Patients
at Risk, n
T-DM1
Trastuzumab
HR: 0.70 (95% CI: 0.47-1.05; P = .08)
Events, n (%)
T-DM1
(n = 743)
42 (5.7)
Trastuzumab
(n = 743)
56 (7.5)
Distant Recurrence OS

KATHERINE: Safety
AE, n (%) T-DM1 (n = 740) Trastuzumab (n = 720)
Any AE 731 (98.8) 672 (93.3)
Grade ≥ 3 AEs 190 (25.7) 111 (15.4)
Serious AEs 94 (12.7) 58 (8.1)
AE leading to treatment discontinuation
 PLT count decrease
 Blood bilirubin increase
 AST increase
 ALT increase
 Peripheral sensory neuropathy
 Ejection fraction decrease
133 (18.0)
31 (4.2)
19 (2.6)
12 (1.6)
11 (1.5)
11 (1.5)
9 (1.2)
15 (2.1)
0
0
0
0
0
10 (0.4)
AE leading to death 1 (0.1)* 0
*Intracranial hemorrhage after a fall with 55,000 platelets/μL.

KATHERINE: Treatment Exposure
Parameter, n (%) T-DM1 (n = 740) Trastuzumab (n = 720)
Treatment cycles completed
 7
 14
637 (86.1)
528 (71.4)
664 (92.2)
583 (81.0)
T-DM1 dose reduction
 None
 1 level (3.0 mg/kg)
 2 levels (2.4 mg/kg)
634 (85.7)
77 (10.4)
29 (3.9)
NA

KATHERINE: All-Grade AEs Occurring in ≥ 15% of Patients
in Either Arm
Slide credit: clinicaloptions.comGeyer. SABCS 2018. Abstr GS1-10. Reproduced with permission. von Minckwitz. NEJM. 2018;[Epub].
11
9
2
Patients(%)
4
3
6
5
6
5
2
2
34
26
7
50
33
15 42
33
8
29
6
14
9
28
23
5
28
22
6
21
16
5
26
19
7
28
17
10
25
13
11
23
18
4
7
5
19
12
5
8
7
13
10
3
22
19
2
17
14
3
Grade 2
Grade ≥ 3
Grade 1
T-DM1 (n = 740) Trastuzumab (n = 720)
Grade 2
Grade ≥ 3
Grade 1
60
40
20
0
17
13
4
15
4
11

KATHERINE: Conclusions
 In patients with HER2+ EBC who had residual invasive disease after
neoadjuvant chemotherapy plus HER2-targeted therapy and surgery,
T-DM1 significantly prolonged IDFS compared with trastuzumab
‒ HR: 0.50 (95% CI: 0.39-0.64; P < .001)
‒ Benefit with T-DM1 consistent across examined subgroups
 No unexpected safety signals
 Longer follow-up needed for OS
 Study investigators conclude that T-DM1 will likely represent a new
standard of care in this population

TAM-01: Low-Dose Tamoxifen vs Placebo as Adjuvant
Therapy for EBC
 Multicenter, randomized, triple-blind phase III study
 Primary endpoint: incidence of invasive breast cancer
 Secondary endpoints including: safety, patient-reported outcomes,
adherence
Women < 75 yrs of age with
breast intraepithelial neoplasia
(ADH, LCIS, or ER+/unknown
DCIS) and prior surgery
(N = 500)
Tamoxifen 5 mg PO QD for 3 Yrs
(n = 253)
Placebo for 3 Yrs
(n = 247)
Slide credit: clinicaloptions.comDeCensi. SABCS 2018. Abstr GS3-01. NCT01357772.
Visit and QoL every 6 mos; mammography every yr.
Follow-up for
at least 2 yrs

TAM-01: Baseline Characteristics
Slide credit: clinicaloptions.comDeCensi. SABCS 2018. Abstr GS3-01.
Characteristic Tamoxifen (n = 253) Placebo (n = 247)
Mean age, yrs (SD) 54 (9.6) 54 (9.1)
Premenopausal, % 46 44
Mean BMI (SD) 25.7 (4.8) 25.3 (4.2)
ADH, % 20 20
LCIS, % 11 10
DCIS, % 69 70
 ER positive/unknown, % 66/34 67/33
HER2+, % 8 9
Quadrantectomy/mastectomy, % 84/16 82/18
Radiotherapy, % 43 43

TAM-01: Recurrence
 Median follow-up: 5.1 yrs (IQR: 3.9-6.3)
Outcome, n
Tamoxifen
(n = 253)
Placebo
(n = 247)
HR (95% CI) P Value
All breast events* 14 28 0.48 (0.26-0.92) .024
Contralateral breast cancer 3 12 0.24 (0.07-0.87) .018
*Rate: 11.6 vs 23.9/1000 PY.

TAM-01: On-Study Tumor Development
Characteristic
Tamoxifen
(n = 14)
Placebo
(n = 28)
Invasive, n 3 10
DCIS, n 11 18
Median tumor diameter, mm (IQR) 10 (8-17) 16 (6-22)
Median ER, % (IQR) 83 (70-95) 90 (60-95)
Median PgR, % (IQR) 60 (5-80) 23 (0-90)
HER2+, % 20 16
Median Ki67, % (IQR) 24 (11-32) 20 (13-28)

TAM-01: Safety, QoL
 No difference between arms in
patient-reported vaginal
dryness or pain at intercourse,
musculoskeletal pain/arthralgia
 Patient-reported frequency of
daily hot flashes significantly
increased with low-dose
tamoxifen vs placebo (P = .05)
‒ Difference disappeared when
intensity of hot flash was added
to comparison of frequency
Serious AE, n Tamoxifen Placebo
Endometrial cancer 1 0
DVT or PE 1 1
Other neoplasms 4 6
Coronary heart disease 2 2
Other 3 5
Death 1 2
Total 12 16

TAM-01: Adherence, Treatment Impact
Adherence Measure, %
Tamoxifen
(n = 253)
Placebo
(n = 247)
Persistent use of
treatment > 2.5 yrs*
64.8 60.7
*P = .39
Impact Measure Tamoxifen
Number to treat for benefit,† n 22
Number to treat before harm,‡ n 218
Likelihood of benefit 10x
Based on 5-yr cumulative incidence of †breast events
(6.4% vs 11.0% with PBO) or ‡serious AEs (0.87% vs
0.41% with PBO).

TAM-01: Conclusions
 Following surgery in patients with intraepithelial neoplasia, 3 yrs of low-dose
tamoxifen (ie, 5 mg/day) halved breast cancer recurrence vs placebo
‒ HR: 0.48 (95 CI: 0.26-0.92; P = .024)
 Risk of contralateral breast cancer reduced by 76% with low-dose tamoxifen
vs placebo
 Similar rates of serious AEs (eg, endometrial cancer, DVT or PE) and most
menopausal symptoms between arms
‒ Frequency of self-reported hot flashes higher with tamoxifen vs placebo
 Study investigators conclude that low-dose tamoxifen provides a valid
preventative option to avoid recurrence in this population

AERAS: Extended Adjuvant Therapy With Anastrozole
for Postmenopausal Women With HR-Positive EBC
 Prospective, multicenter, randomized, open-label phase III study
 Primary endpoint: DFS
 Secondary endpoints including: OS, distant DFS, safety
Postmenopausal women with
stage I-III HR+ breast cancer
who were disease free after
adjuvant anastrozole therapy*
(N = 1683)
Continue Anastrozole† for up to 5 Additional Yrs
(n = 840)
No Further Adjuvant Therapy
(n = 843)
Slide credit: clinicaloptions.comOhtani. SABCS 2018. Abstr GS3-04. JPRN-UMIN000000818.
*As monotherapy for 4 yrs 9 mos to 5 yrs 2 mos or for > 2 yrs after tamoxifen for a total of 5 yrs adjuvant therapy. †1 mg PO QD.
Stratified by nodal status, prior adjuvant chemotherapy,
choice of tamoxifen or anastrozole, institution

AERAS: Baseline Characteristics
Slide credit: clinicaloptions.comOhtani. SABCS 2018. Abstr GS3-04.
Characteristic
Continue
Anastrozole
(n = 840)
Stop
Therapy
(n = 843)
Median age, yrs 64.3 64.5
BMI 23.3 23.3
T-stage, n (%)
 T1
 T2
 T3/T4
449 (53.4)
358 (42.6)
33 (3.9)
437 (51.8)
378 (44.8)
28 (3.3)
N-stage, n (%)
 N0
 N1
 N2
650 (77.3)
171 (20.3)
19 (2.2)
667 (79.1)
163 (19.3)
13 (1.5)
Characteristic, n (%)
Continue
Anastrozole
(n = 840)
Stop
Therapy
(n = 843)
Hormone receptor
 ER+
 PgR+
830 (98.8)
618 (73.5)
836 (99.1)
627 (74.3)
Radiotherapy 456 (54.2) 457 (54.2)
Adjuvant
chemotherapy
328 (39) 332 (39.3)
Endocrine therapy
 Anastrozole
 Tamoxifen, then
anastrozole
774 (91.1)
75 (8.9)
772 (91)
76 (9)

AERAS: Patient Disposition
Outcome Continue Anastrozole Stop Therapy
Median treatment duration, yrs 4.9 4.9
Completed 5 yrs treatment in study, % 70.1 75.2
Reason for early termination, %
 AEs
 Patient refusal
 Changing hospital
 Breast cancer recurrence
 Second cancer (not breast related)
 Other
9.6
7.4
2.2
5.4
1.9
2.9
0
3
2.2
11.3
5.4
4.1

AERAS: Disease-Free Survival
Slide credit: clinicaloptions.comOhtani. SABCS 2018. Abstr GS3-04. Reproduced with permission.
DFS(%)
Days From Randomization to First Event
831
828
755
773
687
728
600
643
522
570
228
257
Patients at
Risk, n
Continue
Stop
1000 2000
100
80
60
40
20
0
3000 40000
5-yr DFS rate, %
Events, n
91.9
51
Stop
Therapy
(n = 828)
84.4
98
Continue
Anastrozole
(n = 831)
HR: 0.548, P = .0004

AERAS: DFS by Subgroup
Subgroup
Overall
Prior endocrine therapy
Anastrozole
Tamoxifen, then anastrozole
Age
< 60 yrs
≥ 60 yrs
BMI
< 25
≥ 25
T-stage
T1
≥ T2
N-stage
N0
≥ N1
Hormone status
ER+PgR+
Any negative
Prior chemotherapy
No
Yes
Continue Better Stop Better
Continue
51/831 (6.1)
47/757 (6.2)
4/74 (5.4)
8/200 (4.0)
43/631 (6.8)
40/598 (6.7)
11/233 (4.7)
21/427 (4.9)
30/375 (8.0)
36/621 (5.8)
15/181 (8.3)
39/580 (6.7)
12/222 (5.4)
27/488 (5.5)
24/313 (7.7)
0.55 (0.39-0.77)
0.55 (0.39-0.78)
0.60 (0.18-1.99)
0.46 (0.20-1.06)
0.57 (0.40-0.83)
0.58 (0.40-0.86)
0.47 (0.23-0.96)
0.60 (0.35-1.04)
0.52 (0.34-0.81)
0.51 (0.34-0.76)
0.69 (0.35-1.33)
0.64 (0.43-0.95)
0.38 (0.19-0.73)
0.58 (0.36-0.92)
0.53 (0.32-0.86)
HR (95% CI)Events/Patients, n/N (%)
Stop
97/829 (11.7)
89/753 (11.8)
8/76 (10.5)
18/204 (8.8)
79/625 (12.6)
72/599 (12.0)
25/230 (10.9)
36/415 (8.7)
61/384 (15.9)
76/634 (12.0)
21/165 (12.7)
67/587 (11.4)
30/212 (14.2)
50/487 (10.3)
47/311 (15.1)
P Value*
.0006
.5677
.0487
.3088
.0005
.2881
.6668
.0205
*Test of interaction between treatment and
each subgroup unadjusted for multiplicity.
0.25 0.5 1 1.5 2 3

AERAS: Distant Disease–Free Survival and OS
DDFS OS
DDFS(%)
Days
HR: 0.514 (P = .0077)
5-yr DDFS rate, %
Events, n
97.2
23
Stop
Therapy
(n = 828)
94.3
47
Continue
Anastrozole
(n = 831)
831
828
755
773
687
728
600
643
522
570
228
257
Patients
at Risk, n
Continue
Stop
OS(%)
Days
831
828
755
773
687
728
600
643
522
570
228
257
Patients
at Risk, n
Continue
Stop
5-yr OS rate, %
Events, n
99.5
4
Stop
Therapy
(n = 828)
99.6
3
Continue
Anastrozole
(n = 831)
100
80
60
40
20
0
HR: 1.389 (P = .665)
1000 2000 3000 40000
100
80
60
40
20
0
1000 2000 3000 40000

AERAS: Safety, Event Overview
Predefined
AE, %
Continue
Anastrozole
(n = 783)
Stop
Therapy
(n = 783)
Any Gr ≥ 3 Any Gr ≥ 3
Bone fractures 2.8 0.5 1.1 0.1
Osteoporosis 33 0.3 28 0.1
Arthralgia 19.2 0.8 11.7 0.1
Stiff joints 11.7 0.3 4.9 0
Hot flashes 6.7 0.5 3.2 0
Headache 2.1 0.1 1.8 0
Event, n (%)
Continue
Anastrozole
(n = 831)
Stop
Therapy
(n = 828)
Local recurrence 15 (1.8) 32 (3.8)
Distant recurrence 23 (2.7) 47 (5.6)
Contralateral breast
cancer
6 (0.7) 7 (0.8)
Second primary
cancer
13 (1.5) 35 (4.3)
Death 4 (0.4) 3 (0.3)

AERAS: Conclusions
 In postmenopausal women with primary HR+ breast cancer who were disease free
after 5 yrs of adjuvant endocrine therapy, an additional 5 yrs of anastrozole
significantly prolonged DFS compared with patients who stopped therapy
‒ 5-yr DFS rate: 91.9% vs 84.4%, respectively (HR: 0.548; P = .0004)
 DDFS also significantly prolonged with anastrozole extension vs discontinuation
‒ 5-yr DDFS rate: 97.2% vs 94.3%, respectively (HR: 0.514; P = .0077)
 5-yr OS rates comparable between arms
 Local and distant recurrence, second primary cancers numerically less frequent
with anastrozole extension vs discontinuation
 AE rates numerically higher with anastrozole extension vs discontinuation

Locally Advanced/
Metastatic Breast Cancer

SOLAR-1: Alpelisib + Fulvestrant for Men and
Postmenopausal Women With HR-Positive ABC
 International, randomized, double-blind phase III study
Men or postmenopausal women with
HR+/HER2- advanced breast cancer
and recurrence/progression on or after
prior aromatase inhibitor therapy;
ECOG PS 0/1; measurable disease or ≥
1 predominantly lytic bone lesion
(N = 572)
Alpelisib† + Fulvestrant‡
(n = 169)
Placebo + Fulvestrant‡
(n = 172)
Slide credit: clinicaloptions.comJuric. SABCS 2018. Abstr GS3-08.
*By tumor tissue.
†300 mg PO QD.
‡500 mg IM on Days 1, 15
of first 28-day cycle, then on
Day 1 in subsequent cycles.
Stratified by presence of liver/lung metastases, prior CDK4/6 inhibitor treatment
Alpelisib† + Fulvestrant‡
(n = 115)
Placebo + Fulvestrant‡
(n = 116)
PIK3CA
mutant*
(n = 341)
PIK3CA
non-mutant*
(n = 231)
 Primary endpoint: PFS in PIK3CA-mutant cohort (locally assessed)
 Secondary endpoints including: OS, PFS in PIK3CA non-mutant cohort, PFS by
PIK3CA status as evaluated with ctDNA, ORR/CBR, safety

SOLAR-1: PFS in PIK3CA-Mutant Cohort (Locally Assessed)
Slide credit: clinicaloptions.comJuric. SABCS 2018. Abstr GS3-08. André. ESMO 2018. Abstr LBA3_PR.
PFS Alpelisib + Fulvestrant (n = 169) Placebo + Fulvestrant (n = 172)
Median, mos (95% CI) 11.0 (7.5-14.5) 5.7 (3.7-7.4)
HR (95% CI) 0.65 (0.50-0.85); P = .00065
Events, n (%)
 Progression
 Death
 Censored
103 (60.9)
99 (58.6)
4 (2.4)
66 (39.1)
129 (75.0)
120 (69.8)
9 (5.2)
43 (25.0)
 Similar PFS outcome for alpelisib + fulvestrant vs placebo + fulvestrant in
retrospective analysis of PIK3CA mutation status via ctDNA testing
‒ Median PFS: 10.9 vs 3.7 mos, respectively; HR: 0.55
 More patients with BL measurable disease experienced decreases in tumor burden
with alpelisib + fulvestrant vs placebo + fulvestrant (75.9% vs 43.5%, respectively)

SOLAR-1: PFS by Prior Therapy in PIK3CA-Mutant Cohort
Median PFS, Mos
Alpelisib +
Fulvestrant
Placebo +
Fulvestrant
HR (95% CI)
First line (n = 177)
 Endocrine sensitive* (n = 39)
 Endocrine resistant† (n = 138)
11.0
22.1
9.0
6.8
19.1
4.7
0.71 (0.49-1.03)
0.87 (0.35-2.17)
0.69 (0.46-1.05)
Second line‡ (n = 161) 10.9 3.7 0.61 (0.42-0.89)
Prior CDK4/6i therapy
 Yes (n = 20)
 No (n = 321)
5.5
11.0
1.8
6.8
0.48 (0.17-1.36)
0.67 (0.51-0.87)
*PD > 1 yr after (neo)adjuvant ET; excluded later per protocol amendment.
†PD ≤ 1 yr after (neo)adjuvant ET.
‡PD > 1 yr after (neo)adjuvant ET and while on/after 1 line of ET for ABC or newly diagnosed ABC with PD on/after 1 line of ET.

SOLAR-1: Interim OS in PIK3CA-Mutant Cohort
 Data cutoff (June 12, 2018) included 52% of planned events for final OS
analysis
 Median follow-up: 15.9 mos (range: 0.4-31.7)
OS
Alpelisib + Fulvestrant
(n = 169)
Placebo + Fulvestrant
(n = 172)
Median, mos (95% CI) NE (28.1-NE) 26.9 (21.9-NE)
HR (95% CI) 0.73 (0.48-1.10); P = .06

SOLAR-1: AEs Occurring in ≥ 20% of Patients in Either Arm
AE, %
PIK3CA-Mutant Cohort PIK3CA Nonmutant Cohort
ALP + FUL (n = 169) PBO + FUL (n = 171) ALP + FUL (n = 115) PBO + FUL (n = 116)
Any Gr 3 Gr 4 Any Gr 3 Gr 4 Any Gr 3 Gr 4 Any Gr 3 Gr 4
Any 99.4 68.6 11.8 88.9 26.9 6.4 99.1 58.3 11.3 96.6 35.3 3.4
Hyperglycemia 65.1 32.0 4.7 8.8 0 0.6 61.7 33.9 2.6 11.2 0.9 0
Diarrhea 54.4 7.7 0 11.1 0.6 0 62.6 5.2 0 22.4 0 0
Nausea 45.6 2.4 0 19.9 0 0 43.5 2.6 0 25.9 0.9 0
Rash 39.6 13.0 0 6.4 0.6 0 29.6 5.2 0 5.2 0 0
Decreased appetite 33.7 0.6 0 7.6 0 0 38.3 0.9 0 14.7 0.9 0
Stomatitis 26.6 3.0 0 6.4 0 0 21.7 1.7 0 6.0 0 0
Decreased weight 26.6 3.6 0 0.6 0 0 27.0 4.3 0 4.3 0 0
Vomiting 25.4 0 0 9.4 0 0 29.6 1.7 0 10.3 0.9 0
Fatigue 23.7 3.0 0 15.2 0 0 25.2 4.3 0 19.8 2.6 0

SOLAR-1: Hyperglycemia in Alpelisib-Containing Arm
 Glucose > 160 mg/dL typically
observed by Day 15
‒ Median duration: 10 days
 Fasting plasma glucose and A1C
spikes highest in alpelisib
recipients who were diabetic
(4%) or prediabetic (56%) at BL
‒ 87% with hyperglycemia
received antidiabetic
medication, typically metformin
Event, %
Alpelisib +
Fulvestrant
Hyperglycemia serious AEs 10.6
Hyperglycemia-related AEs
 Dose interruption 40.6
 Dose adjustment 43.9
 Discontinuation 6.3

SOLAR-1: Conclusions
 In patients with HR+/HER2- PIK3CA-mutant advanced breast cancer and
recurrence/progression on or after prior aromatase inhibitor therapy, addition of
alpelisib to fulvestrant significantly prolonged PFS vs placebo plus fulvestrant
‒ PIK3CA-mutant assessed by tissue (HR: 0.65; 95% CI: 0.50-0.85; P = .00065)
‒ Benefit evident regardless of line of therapy and/or prior CDK4/6 inhibitor treatment;
for PIK3CA-mutant determined by ctDNA
 OS data not yet mature
 Hyperglycemia common on-target adverse event with alpelisib, typically observed
early in treatment and transient
‒ Manageable with oral antidiabetic therapy

IMpassion130: Biomarker Analysis in TNBC Patients
Receiving Frontline Atezolizumab + Nab-Paclitaxel
 International, randomized, double-blind phase III study[1,2]
Patients with previously untreated*
metastatic or unresectable locally
advanced triple-negative breast cancer
(N = 902)
Until PD or
unacceptable toxicity
Atezolizumab† + Nab-Paclitaxel‡
(n = 451)
Placebo + Nab-Paclitaxel‡
(n = 451)
Slide credit: clinicaloptions.com1. Schmid. NEJM. 2018;379:2108. 2. Emens. SABCS 2018. Abstr GS1-04.
*Prior chemo in curative setting permitted if tx-free for ≥ 12 mos. †840 mg IV Q2W. ‡100 mg/m2 IV on D1, 8, and 15 of 28-day cycle.
Stratified by prior taxane use, liver metastases, and PD-L1 expression on IC
 Coprimary endpoints: PFS, OS in ITT population and PD-L1+ subgroup (≥ 1% on
tumor infiltrating IC)[1]
 Exploratory analysis: efficacy by PD-L1 expression on TC, intratumoral CD8+ T-cells,
sTILs, BRCA1/2 status[2]

IMpassion130: PD-L1 Expression
Slide credit: clinicaloptions.comEmens. SABCS 2018. Abstr GS1-04.
*IC0: < 1%; IC1: ≥ 1% and < 5%; IC2: ≥ 5% and < 10%; IC3: ≥ 10%. †TC-negative: < 1%; TC-positive: ≥ 1%.
Prevalence of PD-L1 Expression Subgroup, %
Biomarker-Evaluable Population
(n = 900)
IC*
 0 59
 1 27
 2/3 14
TC†
 Negative 91
 Positive 9
•Simultaneously IC1/2/3 7

IMpassion130: PFS by PD-L1 Expression
Slide credit: clinicaloptions.comEmens. SABCS 2018. Abstr GS1-04. Reproduced with permission.
PFS
PD-L1 IC Positive PD-L1 IC Negative
Atezo + Nab-P
(n = 185)
PBO + Nab-P
(n = 184)
Atezo + Nab-P
(n = 266)
PBO + Nab-P
(n = 267)
Median, mos (95% CI) 7.5 (6.7-9.2) 5.0 (3.8-5.6) 5.6 (5.5-7.3) 5.6 (5.4-7.2)
HR (95% CI) 0.62 (0.49-0.78); P < .0001 0.94 (0.78-1.13); P = .5152
P value* .0055
Mos
0 3 6
100
80
60
40
20
0
PFS(%)
9 12 15 18 21 2724 30 33
*For interaction (treatment x PD-L1 IC).
Atezolizumab + nab-P (PD-L1 IC+)
Atezolizumab + nab-P (PD-L1 IC-)
Placebo + nab-P (PD-L1 IC+)
Placebo + nab-P (PD-L1 IC-)

IMpassion130: OS by PD-L1 Expression
0 3 6
100
80
60
40
20
0
OS(%)
9 12 15 18 21 2724 30 33 36
Mos
OS
PD-L1 IC Positive PD-L1 IC Negative
Atezo + Nab-P
(n = 185)
PBO + Nab-P
(n = 184)
Atezo + Nab-P
(n = 266)
PBO + Nab-P
(n = 267)
Median, mos
(95% CI)
25.0
(22.6-NE)
15.5
(13.1-19.3)
18.9
(15.5-22.0)
18.4
(16.4-24.7)
HR (95% CI) 0.62 (0.45-0.86); P = .0035 1.02 (0.79-1.31); P = .9068
P value* .0178
*For interaction (treatment x PD-L1 IC).
Atezolizumab + nab-P (PD-L1 IC+)
Atezolizumab + nab-P (PD-L1 IC-)
Placebo + nab-P (PD-L1 IC+)
Placebo + nab-P (PD-L1 IC-)

P Value
.90
≤ .005
.26
.07
IMpassion130: Survival by PD-L1 IC Subgroup
PD-L1
Status
IC0
IC1
IC2/3
All
Atezo + Nab-P Better Placebo + Nab-P Better
0.2 1.0 2
n
532
243
125
900
Median, mos
Atezo
5.6
7.4
9.3
7.2
PBO
5.6
3.9
5.7
5.5
PFS
NegPos
HR
(95% CI)
0.93
(0.77-1.12)
0.59
(0.44-0.78)
0.64
(0.42-0.97)
0.79
(0.68-0.92)
P Value
.47
≤ .005
.03
≤ .005
0.2 1.0 2
Median, mos
Atezo
18.9
23.4
25.0
21.3
PBO
18.4
14.4
21.1
17.6
OS
HR
(95% CI)
1.02
(0.79-1.31)
0.56
(0.38-0.82)
0.71
(0.39-1.30)
0.83
(0.68-1.02)
Atezo + Nab-P Better Placebo + Nab-P Better

IMpassion130: Survival by PD-L1 Expression and CD8
Expression, sTIL, or BRCA1/2 Mutation Status
HR (95% CI)*
CD8-/PD-L1 IC+
(n = 37)
CD8+/PD-L1 IC+
(n = 280)
CD8+/PD-L1 IC-
(n = 220)
PFS 0.33 (0.13-0.87); P = .03 0.61 (0.46-0.80); P ≤ .005 0.89 (0.66-1.20); P = .45
OS 0.25 (0.06-1.02); P = .05 0.55 (0.38-0.80); P ≤ .005 0.77 (0.50-1.17); P = .21
HR (95% CI)† sTIL-/PD-L1 IC+
(n = 176)
sTIL+/PD-L1 IC+
(n = 190)
sTIL+/PD-L1 IC-
(n = 94)
PFS 0.74 (0.54-1.03); P = .07 0.53 (0.38-0.74); P ≤ .005 0.99 (0.62-1.57); P = .97
OS 0.65 (0.41-1.02); P = .06 0.57 (0.35-0.92); P = .02 1.53 (0.76-3.08); P = .24
*N = 720; 0.5% cutoff for positive vs negative CD8. †N = 893; 10% cutoff for low vs intermediate/high sTILs. ‡N = 612.
HR (95% CI)‡ BRCA1/2 non-mut/PD-L1 IC+
(n = 257)
BRCA1/2 mut/PD-L1 IC+
(n = 45)
BRCA1/2 mut/PD-L1 IC-
(n = 44)
PFS 0.63 (0.48-0.83); P ≤ .005 0.45 (0.21-0.96); P = .04 0.77 (0.37-1.61); P = .49
OS 0.62 (0.43-0.91); P = .01 0.87 (0.26-2.85); P = .82 0.85 (0.29-2.43); P = .76

IMpassion130: Conclusions
 In patients with untreated metastatic or unresectable locally advanced
triple-negative breast cancer, PD-L1 IC positivity (≥ 1%) predicted
survival benefit with atezolizumab vs placebo addition to nab-paclitaxel
‒ Subgroups positive for intratumoral CD8+ T-cells, sTILs, or BRCA1/2
mutations demonstrated prolonged OS and/or PFS with atezolizumab
only when simultaneously PD-L1 IC+
 Study investigators suggest that PD-L1 IC testing should be routine in
this population to identify individuals who would most benefit from
combination treatment

KEYNOTE-173: Pembrolizumab + Chemotherapy as
Neoadjuvant Therapy for TNBC
 Multicohort, open-label phase Ib study
 Primary endpoint: safety/tolerability
 Secondary endpoints including: pCR rate, ORR, EFS, OS
Slide credit: clinicaloptions.comSchmid. SABCS 2018. Abstr PD5-01. NCT02622074.
All tx given IV. Cyclophosphamide: 600 mg/m2 Q3W. Doxorubicin: 60 mg/m2 Q3W. Nab-P, Pac: Days 1, 8, 15 Q3W. Pembro: 200 mg Day 1 in cycle 1,
then Q3W. Definitive surgery per local standards and tissue collection for pCR 3-6 wks following completion of neoadjuvant therapy.
Pembro + Nab-P 125 mg/m2
Pembro + Nab-P 100 mg/m2 + Carboplatin AUC 6 D1
Pembro + Nab-P 125 mg/m2 + Carboplatin AUC 5 D1
Pembro + Nab-P 125 mg/m2 + Carboplatin AUC 2 D1, 8, 15
Pembro + Paclitaxel 80 mg/m2 + Carboplatin AUC 5 D1
Pembro + Paclitaxel 80 mg/m2 + Carboplatin AUC 2 D1, 8, 15
Pembro
Pembro
Pembro
Pembro
Pembro
Pembro
Pembro + AC
Pembro + AC
Pembro + AC
Pembro + AC
Pembro + AC
Pembro + AC
Cycle 1 Cycle 5 Cycle 9
Cohort A
Cohort B
Cohort C
Cohort D
Cohort E
Cohort F
Adult women
with untreated,
locally advanced
TNBC; ECOG PS
0/1; adequate
organ function
(N = 60)

KEYNOTE-173: Baseline Characteristics
Slide credit: clinicaloptions.comSchmid. SABCS 2018. Abstr PD5-01.
Characteristic
Cohort A
(n = 10)
Cohort B
(n = 10)
Cohort C
(n = 10)
Cohort D
(n = 10)
Cohort E
(n = 10)
Cohort F
(n = 10)
All Pts
(N = 60)
Median age, yrs (range)
53.5
(32-71)
50.0
(32-68)
43.5
(31.51)
41.0
(26-64)
58.0
(34-69)
53.5
(34-65)
48.5
(26-71)
ECOG PS, %
 0
 1
70
30
90
10
90
10
90
10
100
0
90
10
88
12
Primary tumor, %
 T1
 T2
 T3
 T4
10
60
30
0
10
70
20
0
20
60
20
0
0
80
20
0
0
80
20
0
10
40
30
20
8
65
23
3
Nodal involvement, %
 N0
 N1
 N2
10
40
50
40
50
10
40
50
10
40
60
0
40
60
0
30
60
10
33
53
13
Overall stage, %
 II
 III
40
60
90
10
90
10
80
20
100
0
50
50
75
25
PD-L1 status by CPS, %
 ≥ 1%
 < 1%
 Unknown
90
0
10
70
10
20
90
10
0
70
10
20
80
10
10
70
10
20
78
8
13

KEYNOTE-173: Dose-Limiting Toxicities
 Overall DLTs: 22/60 (36.7%)
‒ 0% in cohort E
‒ 20% in cohort A
‒ 40% in cohorts B/F
‒ 60% in cohorts C/D
 Dosing and regimens from
cohorts A/E deemed acceptable
‒ All other cohorts failed to meet
RP2D threshold
 Most frequent DLTs
‒ Febrile neutropenia, n = 9
‒ Neutropenia, n = 7
 DLT severity
‒ Grade 4, n = 11
‒ Grade 5, n = 1
‒ Death due to chemotherapy-
related septic shock in cohort D

KEYNOTE-173: Treatment-Related AEs
 100% of patients experienced
treatment-related AEs
‒ Grade ≥ 3 events reported in
90%
‒ Led to pembrolizumab
discontinuation in 18%
 30% of patients experienced
immune-related AEs
Treatment-Related AEs, %
All Patients
(N = 60)
Any 100
Grade ≥ 3 90
 Neutropenia 73
 Febrile neutropenia 22
 Anemia 20
 Thrombocytopenia 8
Immune-related 30
 Hypothyroidism 8
 Hyperthyroidism 5

KEYNOTE-173: Efficacy
 Overall pCR rate at definitive surgery[1]
‒ ypT0/Tis ypN0: 60% (range: 30% to 80%)
‒ ypT0 ypN0: 57% (range: 20% to 80%)
‒ Highest rates observed in cohorts B-D (ie, patients receiving nab-paclitaxel and
carboplatin in cycles 2-5)
 Patients achieving pCR showed better 12-mo and 24-mo EFS compared with
those who did not[1]
‒ Better EFS (and OS) rates with vs without carboplatin
 Higher pretreatment sTILs and PD-L1 CPS and on-treatment sTILs were
associated with higher pCR rates[2]
Slide credit: clinicaloptions.com1. Schmid. SABCS 2018. Abstr PD5-01. 2. Loi. SABCS 2018. Abstr P3-10-09.

KEYNOTE-173: Conclusions
 In patients with untreated, locally advanced TNBC, preliminary data
suggest promising antitumor activity and manageable toxicity with
neoadjuvant pembrolizumab + chemotherapy according to
investigators[1]
‒ DLTs in 36.7% of patients
‒ Higher pCR and extended EFS and OS in cohorts receiving carboplatin
 Exploratory analyses suggest that higher pretreatment sTIL level or
PD-L1 CPS may predict higher pCR/ORR[2]
 Phase III KEYNOTE-522 examining neoadjuvant pembrolizumab +
chemotherapy in patients with high-risk, early-stage TNBC ongoing[3]
Slide credit: clinicaloptions.com1. Schmid. SABCS 2018. Abstr PD5-01. 2. Loi. SABCS 2018. Abstr P3-10-09. 3. NCT03036488.

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