Benz®Metastasic.TNCB.Cancer.2019.pptx

1. MEDICAL ONCOLOGY
Juan Pablo Benites M.D.
RESIDENT DOCTOR-4thyr. Perú
St Joseph Hospital - Hamilton Health Sciences
2019.Ontario.Canada©
UpToDate: Therapy in the
Metastasic TNBC

2. © 2019 (Mount Sinai Expert Guides) William K. Oh, Ajai Chari - Mount Sinai Expert Guides Oncology-Wiley-Blackwell
Definition of disease
 Breast cancers arise in the epithelial cells that line milk ducts or in breast alveolar lobules.
 Breast cancers consist of two major categories: invasive and noninvasive.
– Invasive cancers include invasive ductal, lobular, mucinous, tubular, medullary, and papillary
cancers.
 Invasive ductal carcinoma (IDC ó CID) accounts for approximately 70% to 80% of all
cases.4
 Germline mutations of BRCA1 and BRCA2 represent about 5–10% of all breast cancers.4
 BRCA1 on chromosome 17q21 and BRCA2 on chromosome 13q12.3 proteins are
involved in DNA repair.
 The lifetime risk of developing breast cancer by 80% (BRCA1) and 60% (BRCA2), and
ovarian cancer by 54% (BRCA1) and 23% (BRCA2).

3. 1. NIH SEER Cancer Stat Facts: Breast Cancer. Available at: https://seer.cancer.gov/statfacts/html/breast.html
Data source: Globocan 2018 © https://gco.iarc.fr/today/
Incidence/ Prevalence
 Perú 2018 incidence and mortality of female breast cancer :
– 6,985 new cases/yr
– 1,858 deaths/yr
– 40.0 of estimated standardized incidence rates
 Worldwide 2018 incidence and mortality:
– 2.08 million new cases/yr. (11.6%)/ 2th most common cause of incidence
– 626,679 deaths/yr. (6.6%)/ 5th most common cause of cancer death
– It is estimated that ~ 260,000 new cases of Breast Cancer will be diagnosed in the US in
2019.1

4. Female Breast Cancer
 Races with high incidence: Non-Hispanic (132.6), White (130.5), Black (124),
Asian (124), Hispanic (97.2).1
 Median Age At Diagnosis 62yrs (frequently diagnosed among people aged 55-64).1
 Median Age At Death 68yrs (deaths is highest among people aged 65-74).1
 Localized (62%); Regional (30%); Advanced Stage (6%); Unknown (2%).2
 5-Year OS in localized and advanced disease is 98.8% and 27.4%; respectively.3
 In 2016, there were an estimated 3,477,866 women living with female breast cancer in
the United States.1
1 © 2019 Based on data from SEER 2012-2016 All Races, Females.
2., 3 © 2019 Based on data from SEER 18 2009-2015, All Races, Females
4 © 2019 (Mount Sinai Expert Guides) William K. Oh, Ajai Chari - Mount Sinai Expert Guides Oncology-Wiley-Blackwell
Data source: The Surveillance, Epidemiology, and End Results (SEER). https://seer.cancer.gov

5. Screening
1 © 2016 N. Ohuchi, Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan (J-START):
a randomised controlled trial. Lancet., 387 (2016), pp. 341-348
2 © 2019 (Mount Sinai Expert Guides) William K. Oh, Ajai Chari - Mount Sinai Expert Guides Oncology-Wiley-Blackwell
Mammography, S:77% E: 91,4% , Mammography plus + Ultrasound S: 91,1% E: 87,7%.1
Is indicated in women ≥50 years. Associated with a 15–30% decrease in breast cancer mortality
VPP of the biopsy was 22.6% for mammography, 8.9% for ultrasound and 11.2% for mammography plus ultrasound.
Breast magnetic resonance imaging (MRI) in Invasive cancers S: 100% E: 86-100% VPN: 100%.2
More than 16% of contralateral metachronous cancers have reported metastasis.
Annual breast MRI for high risk women as defined by the following:
- Known BRCA mutation carriers, start at age 25. - Lifetime risk ≥20%.
- Untested and first degree relative of BRCA carrier, start at age 25.
- Chest irradiation between ages 10 and 30 years. - Genetic syndromes (e.g. Cowden, Li–Fraumeni).

6. Primary prevention
1 https://bcrisktool.cancer.gov/
© 2019 (Mount Sinai Expert Guides) William K. Oh, Ajai Chari - Mount Sinai Expert Guides Oncology-Wiley-Blackwell
 Breastfeeding for prolonged durations.
 Prophylactic bilateral mastectomy: reduces the risk of breast cancer by 99% in BRCA
germline mutation carriers.
 Prophylactic bilateral salpingoopherectomy: decreases risk of ovarian cancer by 99%
in BRCA mutation carriers.
 Primary chemoprevention is indicated for women with:
- A first degree relative with breast or ovarian cancer,
- History of thoracic irradiation,
- BRCA mutation carriers,
- LCIS, atypical hyperplasia or Gail Model risk assessment tool.a
a. predicting a 5-year breast cancer risk ≥1.7%. Five years of tamoxifen, raloxifene, or the aromatase
inhibitors exemestane or anastrozole reduces the risk of developing breast cancer by 50–75%.

7. Histologic Grade (G); Invasive Cancer (Scarff-Bloom-Richardson [SBR] Grading System, Nottingham Modification)
GX Grade cannot be assessed
G1 Low combined histologic grade (favorable); SBR score of 3-5 points
G2 Intermediate combined histologic grade (moderately favorable); SBR score of 6-7 points
G3 High combined histologic grade (unfavorable); SBR score of 8-9 points
cN (Regional Lymph Nodes)
cN0
No regional lymph node metastases (by imaging
or clinical examination)
cN1
to Metastases to movable ipsilateral level I, II
axillary lymph node(s)
cNmi Micrometastasis (200cells)> 0.2mm to 2 mm
cN2a
Metastases in ipsilateral level I, II axillary lymph
nodes fixed to one another (matted) or to other
structures
cN2b
Metastases only in ipsilateral internal mammary
nodes in the absence of axillary lymph node
metastases
cN3a Metastases in ips. infraclavicular lymph node(s)
cN3b
Metastases in ipsilateral internal mammary
lymph node(s) and axillary lymph node(s)
cN3c
Metastases in ipsilateral supraclavicular lymph
node(s)
TNM Staging System
© 2019 National Comprehensive Cancer Network®
T (tumor)
Tis DICS, LCIS, Paget nipple
T1mi ≤ 0.1 cm
T1
T1a ≤ 0.5 cm
T1b > 0.5 – 1 cm
T1c > 1 cm - 2 cm
T2 > 2 cm - 5 cm
T3 > 5 cm
T4
T4a Extension to chest wall
(doesn´t include
pectoralis muscle
invasión only)
T4b Ulceration, ipsilateral
satellite skin nodules, or
skin oedema ´including
peau d´orange
T4c Both T4a and T4b are
present
T4d Inflammatory carcinoma
TNM Stage
0 TisN0
IA T1N0
IB
T0N1mi
T1N1mi
IIA
T0N1
T1N1
T2N0
IIB
T2N1
T3N0
IIIA
T1N2
T2N2
T3N1
T3N2
IIIB
T4N0
T4N2
IIIC N3, Any T
IV M1
Level 2 nodes
Level 3 nodes
Level 1 nodes
Interpectoral
(Rotter) nodes
Internal
mammary nodes
Infraclavicular
nodes
Supraclavicular
nodes
i
ii
iii
American Joint Committee on Cancer (AJCC)

8. Luminal A Luminal B
Luminal
HER2
HER2
enriched
Triple negative/
basal like
Frequency1 ∼67% ∼10% ∼4% ∼10%
Receptors
ER + + + – –
PR +/– +/– +/– – –
HER2 – – + + –
Grade Low Mod–high Mod–high High High
Ki-67a Low High High High High
Mutationsb
PI3K (49%)
PTENc (13%)
P53 (12%)
PI3K (32%)
P53 (32%)
PTENc (24%)
P53 (75%)
PI3K (42%)
PTENc (19%)
P53 (84%)
PTENc (35%)
PI3K (7%)
Treatments
Anti-estrogens + + + – –
Chemotherapy – +/– +/– + +
HER2 directed – – + + –
Outcome Favorable Intermd Intermd Favorable Poor
Phenotypic classification
1 © 2019 Based on data from SEER 2012-2016 All Races, Females.
© 2019 (Mount Sinai Expert Guides) William K. Oh, Ajai Chari - Mount Sinai Expert Guides Oncology-Wiley-Blackwell
a Ki-67, proliferation marker; low <10–14%; high >14%. b Most frequent mutations based on The Cancer Genome Atlas (TCGA).
c Loss or mutation. d Intermediate.

9. Subtype Localized Regional Distant
HR+/HER2- 100.0% 89.7% 29.8%
HR-/HER2- 91.0% 64.9% 11.2%
HR+/HER2+ 98.3% 89.0% 41.8%
HR-/HER2+ 95.8% 81.6% 36.3%
Unknown 95.6% 77.1% 15.3%
Total 98.8% 85.5% 27.3%
5-Year Relative Survival Percent
© 2019 Based on data from SEER 2012-2016 All Races, Females.
5-Year Relative Survival Percent, Female Breast Subtypes by SEER Summary Stage 2000

10. © 2013, M. Tseng , Distant metastasis in triple-negative breast cancer
© 2010, N Engl J Med 363;20 1. 2007, Bauer KR, Cancer
NO TNCB
Triple Negative CB
Brain
Lung
Liver
Bone
30%
40%
20%
10%
10%
(higher in HER2+ breast cancer)
20%
30%
40%
Sites of First Distant Recurrence in Cases of Metastatic
Organ
Deaths
(%)
Post Metástasis OS (month)
Median p
Bone 83 16.3
0.001
Lung 87.8 16.3
Liver 100 8.9
Pleura 100 7.5
Brain 100 4.3
Bone/ Brain 100 4.3 0.004
Bone/ Liver 100 8.9 0.011
Lung/ Brain 100 4.3 0.001
Lung/ Liver 100 7.5 0.004
Lung/ Pleura 100 7.5 0.029
*Overall survival of triple negative breast cancer patients by the first site (organ) of metastasis.

11. What Is TNBC?
 “Triple negative” = ER negative, PgR negative, HER2 negative
 TNBC accounts for 10% to 17% of all breast carcinomas
 Significantly more aggressive than other molecular subtype tumors
 Majority grade 3 tumors
 Most frequently high-grade invasive ductal carcinomas of no special type.
 BRCA1 + : 20 % TNBC.
Boyle P. Ann Oncol. 2012;23(suppl 6):vi7-vi12.
Anders CK, et al. Clin Breast Cancer. 2009;9(suppl 2):S73-S81. Slide credit: clinicaloptions.com

12. Clinical Characteristics of Metastatic TNBC
 Relapse pattern[1]
– Short disease-free interval
– Increase in visceral mets
– Differs from luminal:
– CNS mets in 46% of cases
1 2 3 4 5 6 7 8 9 10
0.35
0.30
0.25
0.15
0.10
0.05
0
0.20
Annual
Hazard
Rate
0
Yrs After First Surgery
Other (290 of 1421)
Triple negative (61 of 180)
1. Lin NU, et al. Cancer. 2008;113:2638-2645. 2. Liedtke C, et al. J Clin Oncol.
2008;26:1275-1281. 3. Dent R, et al. Clin Cancer Res. 2007;13:4429-4434. Slide credit: clinicaloptions.com
Rate of
Recurrence[2] n Bone, %
Soft
Tissue, %
Viscera, %
TNBC 79 13 13 74
ER+ 123 39 7 54
HER2+ 78 7 12 81
Distant Recurrence Following Surgery[3]

13. TNBC: Classifications
Basallike (BL)
TNBC
Mesenchymallike (ML)
TNBC
Immune-associated
(IM) TNBC
Luminal/apocrine (LA)
TNBC
HER2-enriched (HER2e)
TNBC
Immune
signature
BL2
Cell cycle
DNA damage
Basallike
cytokeratine
Growth
signaling
(EGF,
IGF)
Low
proliferation
AR
pathway
IM
Claudin-
Low BL1
M
Normal BL
LA/LB
HER2e
LAR
PI3K
mutations
EMT signature:
cell motility
growth factor signaling
(TFG6, Notch,
Wnt/β-catenin, Hedgehog)
Angiogenesis
MSL
Lehmann’s classification
PAM50/claudin-low classification
Le Du F. Oncotarget. 2015;6:12890-12908.
This work is licensed under a Creative Commons Attribution 3.0 Unported License. Slide credit: clinicaloptions.com

14. Future aspects of therapeutic strategies:
in patients with TNBC based on its chemosensitivity and immune-molecular heterogeneity.
EGFR, mTOR, MET
inhibitor
PIK3 inhibitor
Androgen blokade
Inmune/FGFR, mTOR, MET
checkpoint inhibitor
Platinum
PARP inhibitor
Inmune
signaling
medullary
breast cancer
EMT
Wnt
Notch
metaplasic breast cancer
https://doi.org/10.2147/CMAR.S146658
PIK3/mTOR, GF, EGFR
inhibitor

15. Ji Hyun Park et al. ESMO Open 2018;3:e000357
Copyright © European Society for Medical Oncology. All rights reserved.
TNBC
Microenvironment
*Combinatorial
Chains
*Combinatorial
Chains
Future aspects of therapeutic strategies:
in patients with TNBC based on its chemosensitivity and immune-molecular heterogeneity.

16. Current Treatment Options for Metastatic TNBC
 Sequential single-agent chemotherapy is the preferred approach for most
pts with metastatic TNBC
– Combination chemotherapy can be used for pts requiring more rapid response
but does not improve OS
Taxanes
Paclitaxel
Nab-paclitaxel
Docetaxel
Anthracyclines
Doxorubicin
Pegylated
liposomal
doxorubicin
Epirubicin
Antimetabolites
Capecitabine
Gemcitabine
Other
Microtubule
Inhibitors
Vinorelbine
Eribulin
Ixabepilone
Platinum Agents
Carboplatin
Cisplatin
Zeichner SB, et al. Breast Cancer (Auckl). 2016;10:25-36.
Wahba HA, et al. Cancer Biol Med. 2015;12:106-116. Slide credit: clinicaloptions.com

17. Clinical Data on the Use of
Immune Checkpoint Inhibitors
for Patients With mTNBC

20. Therapeutic diana Antibody Commercial name Company
PD-1 Pembrolizumab Keytruda Merk
PD-1 Nivolumab Opidivo Bristol-Myers
PD-L1 Atezolizumab Tecentriq Roche
PD-L1 Avelumab -- Merk/Pfizer
PD-L1 Durvalumab -- AstraZeneca
CTLA - 4 Ipilimumab Yervoy Bristol-Myers

21. Atezolizumab + nab-Paclitaxel in Previously
Untreated Advanced TNBC: Updated OS
Analysis of Phase III IMpassion130
CCO Independent Conference Highlights*
of the 2019 ASCO Annual Meeting; May 31 - June 4, 2019; Chicago, Illinois
*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.

22. Atezolizumab + nab-Paclitaxel in Patients With Untreated
Advanced TNBC (IMpassion130): Background
 Clinical outcomes for patients with mTNBC remain poor, with median OS of approximately 15-
18 mos with standard chemotherapy[1-3]
 Phase III IMpassion130 previously demonstrated benefit of adding PD-L1 inhibitor
atezolizumab to nab-paclitaxel in patients with untreated mTNBC and PD-L1+ ICs[4]
– Median PFS in ITT population: 7.2 vs 5.5 mos with placebo (HR: 0.80; P = .002)
– Median PFS in PD-L1+ IC subgroup: 7.5 vs 5.0 mos with placebo (HR: 0.62; P < .001)
– No benefit observed in PD-L1– patients, suggesting benefit driven by PD-L1 positivity
– Based on these findings, atezolizumab + nab-paclitaxel was granted accelerated FDA approval and is
guideline recommended for patients with PD-L1+ mTNBC[5,6]
 Current analysis reports second interim OS analysis (80% mature) from IMpassion130[7]
1. Cardoso. Ann Oncol 2018;29:1634. 2. Gobbini. Eur J Cancer 2018;96:17. 3. Yardley. Ann Oncol 2018;29:1763.
4. Schmid. NEJM. 2018;379:2108. 5. Atezolizumab PI. 6. AGO Recommendations. 2018. 7. Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com

23. Characteristics of the Patients at Baseline.*
Characteristic Intention-to-Treat Population
Atezolizumab+ Placebo+
Nab-Paclitaxel Nab-Paclitaxel (N = 451)
(N = 451)
PD-L1–Positive Subgroup
Atezolizumab+ Placebo+
Nab-Paclitaxel Nab-Paclitaxel (N = 185)
(N = 184)
Age
Median (range) — yr 55 (20–82) 56 (26–86) 53 (26–82) 53 (28–85)
Distribution — no. (%)
18–40 yr 63 (14.0) 51 (11.3) 31 (16.8) 24 (13.0)
41–64 yr 284 (63.0) 285 (63.2) 111 (60.0) 117 (63.6)
≥65 yr 104 (23.1) 115 (25.5) 43 (23.2) 43 (23.4)
Female sex — no. (%) 448 (99.3) 450 (99.8) 184 (99.5) 184 (100)
Race or ethnic group — no. (%)†
White 308 (68.3) 301 (66.7) 125 (67.6) 129 (70.1)
Asian 85 (18.8) 76 (16.9) 38 (20.5) 28 (15.2)
Black 26 (5.8) 33 (7.3) 9 (4.9) 14 (7.6)
Native American 17 (3.8) 23 (5.1) 8 (4.3) 9 (4.9)
Hawaiian or other Pacific Islander 1 (0.2) 0 0 0
Multiple 2 (0.4) 3 (0.7) 0 0
Unknown 12 (2.7) 15 (3.3) 5 (2.7) 4 (2.2)
IMpassion130 Update: Patient Disposition
IMpassion130 Update: Patient Disposition
Slide credit: clinicaloptions.com
Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108.

24. IMpassion130 Update: Patient Disposition
IMpassion130 Update: Patient Disposition
Slide credit: clinicaloptions.com
Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108.
Characteristics of the Patients at Baseline.*
Metastatic disease — no./total no.
(%)
404/450 (89.8) 408/450 (90.7) 162/185 (87.6) 159/183 (86.9)
No. of sites of metastatic disease — no./
total no. (%)
0–3 332/450 (73.8) 341/449 (75.9) 149/185 (80.5) 140/183 (76.5)
≥4 118/450 (26.2) 108/449 (24.1) 36/185 (19.5) 43/183 (23.5)
Site of metastatic disease
Liver — no. (%)§ 126 (27.9) 118 (26.2) 44 (23.8) 39 (21.2)
Bone — no. (%) 145 (32.2) 141 (31.3) 54 (29.2) 49 (26.6)
Brain — no. (%) 30 (6.7) 31 (6.9) 15 (8.1) 11 (6.0)
Lung — no. (%) 226 (50.1) 242 (53.7) 86 (46.5) 98 (53.3)
Lymph node only — no./total no.
(%)
33/450 (7.3) 23/449 (5.1) 18/185 (9.7) 13/183 (7.1)
Previous therapy — no. (%)
Neoadjuvant or adjuvant therapy 284 (63.0) 286 (63.4) 125 (67.6) 117 (63.6)
Taxane§ 231 (51.2) 230 (51.0) 96 (51.9) 94 (51.1)
Anthracycline 243 (53.9) 242 (53.7) 109 (58.9) 101 (54.9)

25. IMpassion130: Study Design
Patients with metastatic or
inoperable, locally advanced
TNBC; no prior therapy for
advanced setting (prior RT or CT
in curative setting allowed
if ≥ 12-mo DFI);
RECIST v1.1 measurable disease;
ECOG PS 0/1;
tumor evaluable for PD-L1*
(N = 902)
Treatment until
PD per RECIST v1.1
or intolerable
toxicity
No crossover
Allowed
Survival follow-up
Atezolizumab 840 mg IV Q2W +
nab-Paclitaxel 100 mg/m2 IV on D1, 8, 15
28-day cycles
(n = 451)
Placebo IV Q2W +
nab-Paclitaxel 100 mg/m2 IV on D1, 8, 15
28-day cycles
(n = 451)
Slide credit: clinicaloptions.com
Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108.
 Randomized, double-blind, placebo-controlled phase III trial
 Coprimary endpoints: PFS and OS (ITT population and PD-L1+ subgroup)
— Prespecified hierarchical OS testing in ITT population; if significant, then PD-L1+ population
Stratified by prior taxane use in curative setting (yes vs no),
liver metastases (yes vs no), PD-L1 IC status (≥ 1% vs < 1%)
*By prospective central testing with SP142 PD-L1 IHC assay.
41% of patients in each arm were PD-L1+ (≥ 1 % IC).

26. IMpassion130 Update: Patient Disposition
 First interim analysis: median f/u, 12.9 mos; 43% deaths in ITT; 59% mature
 Second interim analysis: median f/u, 18.0 mos; 59% deaths in ITT;
80% mature
– Data cutoff: January 2, 2019
Slide credit: clinicaloptions.com
Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108.
Patient Disposition, n (%)
Atezolizumab + nab-Paclitaxel
(n = 451)
Placebo + nab-Paclitaxel
(n = 451)
Patients on study
 Active on treatment
 Active in survival follow-up
39 (9)
133 (30)
13 (3)
135 (3)
Patients who discontinued
 Dead
 Lost to follow-up
255 (57)
24 (5)
279 (62)
24 (5)

27. IMpassion130 Update: OS in ITT Population
Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com
Atezolizumab
+ nab-Paclitaxel
(n = 451)
Placebo
+ nab-Paclitaxel
(n = 451)
Median OS, mos (95% CI) 21.0 (19.0-22.6) 18.7 (16.9-20.3)
24-Mo OS, % (95% CI) 42 (37-47) 39 (34-44)
HR: 0.86 (95% CI: 0.72-1.02; P = .0777)
Patients at Risk, n
Atezo + nab-Pac 451 426 389 342 312 270 235 162 88 56 35 19 8 3 NE
Pbo + nab-Pac 451 420 376 329 291 252 216 145 87 51 33 17 4 1 NE
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos

28. IMpassion130 Update: OS in PD-L1+ Subgroup
Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com
*Not formally tested due to prespecified hierarchical statistical design for trial.
Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com
HR: 0.71 (95% CI: 0.54-0.93)*
Patients at Risk, n
Atezo + nab-Pac 185 177 160 145 135 121 106 69 43 28 21 10 6 3 NE
Pbo + nab-Pac 184 170 147 129 111 93 81 47 26 20 15 10 1 NE NE
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Atezolizumab
+ nab-Paclitaxel
(n = 185)
Placebo
+ nab-Paclitaxel
(n = 184)
Median OS, mos (95% CI) 25.0 (19.6-30.7) 18.0 (13.6-20.1)
24-mo OS, % (95% CI) 51 (43-59) 37 (29-45)

29. IMpassion130 Update: OS by PD-L1 Status
Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com
Median OS, Mos
HR (95% CI)
Atezolizumab
+ nab-Paclitaxel
Placebo
+ nab-Paclitaxel
PD-L1+ 25.0 18.0 0.71 (0.54-0.93)
PD-L1– 19.7 19.6 0.97 (0.78-1.20)
 Treatment benefit limited to PD-L1+ tumors
Atezo + nab-Pac (PD-L1+, n = 185)
Pbo + nab-Pac (PD-L1+, n = 184)
Atezo + nab-Pac (PD-L1–, n = 266)
Pbo + nab-Pac (PD-L1–, n = 267)
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos

30. Atezolizumab + Nab-Paclitaxel in mTNBC: Safety
and Tolerability (Primary Endpoint)
 Additional atezolizumab-related grade 3/4 AEs: syncope, type 1 diabetes mellitus, anemia,
thrombocytopenia/platelet count decreased (n = 3), febrile neutropenia, AST increased,
WBC decreased, and mycoplasmal pneumonia (n = 1 except where indicated)
Atezolizumab-Related AE (Any Grade AE in ≥ 10% of Pts), %
Pts (N = 32)
All Grades Grade ≥ 3
Fatigue 34 --
Neutropenia/decreased neutrophil count 28 9
Pyrexia 25 --
Diarrhea 19 3
Peripheral neuropathy/peripheral sensory neuropathy 19 --
Nausea 16 --
Alopecia 13 --
Headache 13 --
Pruritus 13 --
Adams S, et al. ASCO 2016. Abstract 1009. Slide credit: clinicaloptions.com

31. Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108. Schneeweiss. ASCO 2019. Abstr 1068. Adams. ASCO 2019. Abstr 1067. Slide credit: clinicaloptions.com
IMpassion130 Update: Safety
 Updated safety analysis revealed a profile consistent with primary analysis
 No difference in patient-reported outcomes (HRQoL) between treatment arms
Median follow-up: 15.6 mos (4.5 mos after primary PFS analysis).
All-cause AEs
Treatment-related AEs
Serious AEs
AEs leading to any treatment withdrawal
AESI
AEs leading to Atezo or Pbo withdrawal
AESI requiring systemic corticosteroids
Atezolizumab
+ nab-Paclitaxel
(n = 453)
Placebo
+ nab-Paclitaxel
(n = 437)
Grade 1/2
Grade 3/4
Grade 5
Any grade
0
20
Incidence (%)
20 40
40
60 60 80
80
100 100

32. Atezolizumab + Nab-Paclitaxel in mTNBC:
Efficacy (Secondary Endpoints)
 Among 12 responders, 6 (50%) remain on atezolizumab; 1 for > 17 mos
 Median DoR not reached; PFS and OS data not yet mature
 Responses observed in pts regardless of PD-L1 expression level; trend toward increase in
baseline TILs for responding pts
Best Overall Response (RECIST
v1.1)
First Line
(n = 13)
Second Line
(n = 9)
Third Line+
(n = 10)
All
(N = 32)
Confirmed ORR, % (95% CI) 46 (19-75) 22 (3-60) 40 (12-74) 38 (21-56)
CR, % 8 0 0 3
PR, % 38 22 40 34
SD, % 38 67 30 44
PD, % 15 0 30 16
Missing or not estimable, % 0 11 0 3
Median DoR, mos (range) NE (2.9 to 11.5+) NE (9.1 to 13.1+) NE (1.9+ to 5.6+)
Adams S, et al. ASCO 2016. Abstract 1009. Slide credit: clinicaloptions.com

33. Schmid. ASCO 2019. Abstr 1003. Schmid. NEJM. 2018;379:2108. Schneeweiss. ASCO 2019. Abstr 1068. Adams. ASCO 2019. Abstr 1067. Slide credit: clinicaloptions.com
IMpassion130 Update: summary
Atezo + nP Placebo + nP
ITT population, events/pts, n/n (%) 255/451 (57%) 279/451 (62%)
HR (95% CI); log-rank P 0.86 (0.72, 1.02); 0.078a ―
Median OS (95% CI), mo 21.0 (19.0, 22.6) 18.7 (16.9, 20.3)
2-year OS (95% CI), % 42 (37, 47) 39 (34, 44)
Median follow-up duration, mo 18.5 17.5
PD-L1+ population,b events/pts, n/n (%) 94/185 (51%) 110/184 (60%)
HR (95% CI) 0.71 (0.54, 0.93) ―
Median OS (95% CI), mo 25.0 (19.6, 30.7) 18.0 (13.6, 20.1)
2-year OS (95% CI), % 51 (43, 59) 37 (29, 45)
HRs estimated per stratified Cox model. a Not significant. b PD-L1 on IC ≥ 1% (VENTANA SP142 IHC
assay).

34. IMpassion130 Update: Conclusions
Schmid. ASCO 2019. Abstr 1003. Slide credit: clinicaloptions.com
 Second interim OS analysis of first-line atezolizumab + nab-paclitaxel vs placebo +
nab-paclitaxel for metastatic TNBC was not significant
– Median OS for ITT population: 21.0 vs 18.7 mos (HR: 86; P = .0777)
 Although not formally testable due to trial statistical design, clinical benefit with
combination was observed in PD-L1+ subgroup but not PD-L1– subgroup
– Median OS for PD-L1+ subgroup: 25.0 vs 18.0 mos (HR: 0.71)
 Treatment was well tolerated with no new or late onset safety issues or cumulative
toxicities
 Investigators concluded that atezolizumab + nab-paclitaxel sets new benchmark in
first-line setting for patients with PD-L1+ metastatic TNBC
– First therapy to cross 2-yr landmark OS benefit in this setting (24-mo OS: 51% vs 37%)
– FDA approved and guideline recommended

35. Thank you for your attention