Professor Peter Schmid, FRCP, MD, PhD, Leisha A. Emens, MD, PhD, and Heather L. McArthur, MD, MPH, prepared useful practice aids pertaining to the role of immunotherapy in triple-negative breast cancer for this CME/MOC/CNE activity titled, "On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum." For the full presentation, monograph, complete CME/MOC/CNE information, and to apply for credit, please visit us at http://bit.ly/34aGu95. CME/MOC/CNE credit will be available until December 29, 2020.

1. a
Must consist of ≥2 separate tumor cores from the primary tumor. b
Patients without pCR data for any reason or who received neoadjuvant chemotherapy not specified in the protocol were counted as non-pCR. c
PD-L1 assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured
using the combined positive score (CPS); number of PD-L1+ tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells x100; PD-L1+ = CPS ≥1. d
1 patient from sepsis and multiple organ dysfunction syndrome; 1 patient from pneumonitis. e
1 patient from septic shock.
f
1 patient from pulmonary embolism.
CPS: combined positive score; ECOG PS: Eastern Cooperative Oncology Group performance status; EFS: event-free survival; IA: interim analysis; IHC: immunohistochemistry; ITT: intent to treat; pCR: pathologic complete response; PD-L1: programmed death ligand-1; Q3W: every 3 weeks; QW: every week;
TIL: tumor-infiltrating lymphocyte; TNBC: triple-negative breast cancer; TRAE: treatment-related adverse effect.
1. Schmid P et al. AnnOncol. 2019;30(suppl 5):v851-v934.
Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
PEMBROLIZUMAB AS NEOADJUVANT/ADJUVANT
THERAPY FOR EARLY TRIPLE-NEGATIVE BREAST CANCER
A Trial Overview
PRACTICE AID
KEYNOTE-5221
The first prospective, randomized, placebo-
controlled, phase 3 trial of pembrolizumab in
early TNBC in the neoadjuvant/adjuvant setting
• Age ≥18 y
• Newly diagnosed TNBC
of either T1c N1-2 or
T2-4 N0-2
• ECOG PS 0-1
• Tissue sample for PD-L1
assessmenta
Patients
Pembrolizumab
200 mg Q3W
Placebo
2:1 randomization stratified by nodal status, tumor size, and
carboplatin schedule (QW vs Q3W)
Neoadjuvant Phase Adjuvant Phase
Neoadjuvant
Treatment 1
(cycles 1-4; 12 wk)
Neoadjuvant
Treatment 2
(cycles 5-8; 12 wk)
Adjuvant
Treatment
(cycles 1-9; 27 wk)
Carboplatin
+ paclitaxel
Carboplatin dose: AUC 5 Q3W or AUC 1.5 QW; paclitaxel dose: 80 mg/m2
QW; doxorubicin dose:60 mg/m2
Q3W; epirubicin dose: 90 mg/m2
Q3W; cyclophosphamide dose: 600 mg/m2
Q3W
Doxorubicin/epirubicin
+ cyclophosphamide
Carboplatin
+ paclitaxel
Doxorubicin/epirubicin
+ cyclophosphamide
S
U
R
G
E
R
Y
Pembrolizumab
200 mg Q3W
Placebo
Including radiation
therapy as indicated
Pembro
vs Placebo
Endpoints
Co-primary
• pCR (ypT0/Tis ypN0)
in ITTb
• EFS in ITT
Secondary
• pCR as per ypT0
ypN0 and ypT0/Tis
• OS
• pCR, EFS,b
and
OS in PD-L1+c
• Safety
Exploratory
• Residual cancer burden,
EFS by pCR, and pCR
and EFS by TILs
pCR at IA1
Primary Endpoint (ypT0/Tis ypN0) Secondary Endpoint (ypT0 ypN0) Secondary Endpoint (ypT0/Tis) PD-L1+ (ypT0/Tis ypN0) PD-L1- (ypT0/Tis ypN0)
64.8%
51.2%
13.6 (5.4-21.8)
P = .00055
59.9%
45.3%
14.5 (6.2-22.7)
68.6%
53.7%
14.8 (6.8-23.0)
68.9%
54.9%
45.3%
30.3%
14.2 (5.3-23.1) 18.3 (-3.3-36.8)
PembroPlacebo
EFS at IA2
18-mo Rate
91.3%
85.3%
PembroPlacebo
Therapy Results
HR
(95% CI)
Events, %
Pembro 7.4
0.63
(0.43-0.93)
Placebo 11.8
TRAE, %
Pembro
(n = 781)
Chemo
(n = 389)
Any grade 99.0 99.7
Grade 3-5 76.8 72.2
Led to death 0.3d 0.3e
Led to
discontinuation
of any drug
23.3 12.3
n = 784
n = 390
TRAEs in Neoadjuvant Phase
IA2
TRAEs in Adjuvant Phase
IA2
TRAE, %
Pembro
(n = 547)
Chemo
(n = 314)
Any grade 48.1 43.0
Grade 3-5 5.7 1.9
Led to death 0.2f 0
Led to
discontinuation
of any drug
3.3 1.3

2. a
Centrally evaluated per VENTANA PD-L1 (SP142) IHC assay (double blinded for PD-L1 status); positive = ≥1%; negative = <1%. b
Radiological endpoints were investigator assessed per RECIST v1.1. c
Treatment-related deaths: autoimmune hepatitis, mucosal inflammation/death, and septic shock.
AE: adverse effect; DOR: duration of response; ECOG PS: Eastern Cooperative Oncology Group performance status; IC: tumor-infiltrating immune cell; IHC: immunohistochemistry; ITT: intent to treat; mTNBC: metastatic triple-negative breast cancer; nab-P: nab-paclitaxel; ORR: objective response rate;
PBO: placebo; PD: progressive disease; PD-L1: programmed death ligand-1; RECIST: Response Evaluation Criteria in Solid Tumors; TFI: treatment-free interval; TNBC: triple-negative breast cancer; TRAE: treatment-related adverse effect.
1. Schmid P et al. 43rd European Society for Medical Oncology Congress (ESMO 2018). Abstract LBA1_PR. 2. Schmid P et al. NEnglJMed. 2018;379:2108-2121.
Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
ATEZOLIZUMAB PLUS NAB-PACLITAXEL IN LOCALLY
ADVANCED/METASTATIC TRIPLE-NEGATIVE BREAST CANCER
A Trial Overview
PRACTICE AID
Primary PFS Analysis
Median PFS: ITT Median PFS: PD-L1+
7.2 mo
5.5 mo
Stratified HR = 0.80
(95% CI, 0.69-0.92)
P = .0025
7.5 mo
5.0 mo
21.3 mo
17.6 mo
25.0 mo
15.5 mo
Atezo
+nab-P
Placebo
+nab-P
ORR
56%
46%
Safety Summary
Interim OS Analysis
Median OS: ITT Median OS: PD-L1+
Atezo
+nab-P
Placebo
+nab-P
Atezo
+nab-P
Placebo
+nab-P
Stratified HR = 0.62
(95% CI, 0.49-0.78)
P < .0001
Stratified HR = 0.84
(95% CI, 0.69-1.02)
P = .0840
Stratified HR = 0.62
(95% CI, 0.45-0.86)
ITT PD-L1+
59%
43%
DOR
7.4 mo
DOR
5.6 mo
DOR
8.5 mo
DOR
5.5 mo
TRAE, %
Atezo
+ nab-P
(n = 452)
Placebo
+ nab-P
(n = 438)
Any grade 96 94
Grade 3/4 40 30
Grade 5c
1 <1
All-Cause
AEs, %
Atezo
+ nab-P
(n = 452)
Placebo
+ nab-P
(n = 438)
Any grade 99 98
Grade 3/4 49 42
Grade 5 1 1
Any-Grade
Serious AEs,
%
Atezo
+ nab-P
(n = 452)
Placebo
+ nab-P
(n = 438)
Regardless
of attribution
23 18
TRAEs 12 7
Safety-Evaluable Population
Until RECIST v1.1
PD or toxicity
IMpassion1301,2
The first prospective, randomized, placebo-controlled, phase 3 trial to demonstrate a benefit with first-line immunotherapy in mTNBC
• Metastatic or inoperable
locally advanced TNBC
• No prior therapy for
advanced TNBC (prior
chemo in the curative
setting, including taxanes,
allowed if TFI ≥12 mo)
• ECOG PS 0-1
Patients Atezolizumab 840 mg on d 1 and 15 of 28-d cycle
+ nab-paclitaxel 100 mg/m2
IV on d 1, 8, and 15 of 28-d cycle
Placebo IV on d 1 and 15 of 28-d cycle
+ nab-paclitaxel 100 mg/m2
on d 1, 8, and 15 of 28-d cycle
1:1 randomization stratified by prior taxane use, liver
metastases, and PD-L1 status on IC (≥1% vs <1%)a
Double-blind; no crossover permitted
Atezo
+ nab-P
vs PBO
+ nab-
Endpoints
Co-primary
• PFS and OS in the
ITT and PD-L1+
populationsb
Key Secondary
• ORR, DOR, and
safety
n = 451
n = 451

3. IMMUNO-ONCOLOGY 101
Harnessing the Immune System in the
Treatment of Triple-Negative Breast Cancer
PRACTICE AID
Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most
of Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
Without
Immunotherapy
With
Immunotherapy
MHC
Antigen
TCR
PD-1
PD-L1
Anti–
PD-L1
Anti–
PD-1
Tumor
cell
Tumor escape
Inactivation
of T Cell
Activation
of T Cell
Elimination of
tumor cells
Without
Immunotherapy
With
Immunotherapy
MHC CD80/86
CTLA-4
Anti–
CTLA-4
antibody
APC
Antigen
TCR
Inactivation
of T Cell
Activation
of T Cell
Tumor escape Elimination of
tumor cells
Immune Checkpoint Inhibition in the Treatment of Cancer1
Immune
checkpoints
Proteins on T cells or cancer cells that need to be
activated/inactivated to start/stop an immune response
Examples include PD-1, PD-L1, CTLA-4
Serve as “brakes” that help keep immune responses in
check; can prevent T-cell response against cancer cells
Can be blocked by immune checkpoint inhibitors
The “brakes” on the immune system are released
and T cells are able to attack and kill cancer cells
PD-1/PD-L1 Checkpoint Inhibition2
CTLA-4 Checkpoint Inhibition2
CTLA-4 is a negative
regulator of
costimulation required
for activation of an
antitumor T cell in a
lymph node upon
recognition of
tumor antigen
PD-1 pathway inhibits
signaling downstream of TCR:
TCR triggered by antigen
presented by tumor cell à
negative regulatory
receptor PD-1 expressed à
PD-L1 reactively expressed à
PD-L1 binds to PD-1
Tumor microenvironment Lymphoid tissue
Anti–PD-1
or anti–PD-L1
monoclonal
antibodies
block the
interaction and
negative
regulation
Anti–CTLA-4
monoclonal
antibodies block
negative
regulation by
CTLA-4
T cell inactivated
Tumor escape
T cell activated
Tumor attack
T cell inactivated
Tumor escape
T cell activated
Tumor attack
STOP GO STOP GO

4. IMMUNO-ONCOLOGY 101
Harnessing the Immune System in the
Treatment of Triple-Negative Breast Cancer
PRACTICE AID
APC: antigen-presenting cell; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1;
PD-L1: programmed death ligand 1; TCR: T-cell receptor; TIL: tumor-infiltrating lymphocyte; TNBC: triple-negative breast cancer.
1. Ribas A, Wolchock JD. Science. 2018;359:1350-1355. 2. Adapted from: Soularue E et al. Gut. 2018;67:2056-2067. 3. de la Cruz-Merino et al. Clin Trans Oncol. 2019;21:117-125. 4. Vikas P et al. Cancer Manag Res.
2018;10:6823-6833. 5. Tecentriq (atezolizumab) Prescribing Information. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf. Accessed November 19, 2019. 6. https://www.fda.gov/Drugs/
InformationOnDrugs/ApprovedDrugs/ucm633065.htm. Accessed November 19, 2019.
Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most
of Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
Rationale for Immunotherapy in TNBC3,4
FDA Approval of
Immunotherapy in TNBC5,6
First approval in breast cancer
FDA granted accelerated approval
to atezolizumab in combination with
nab-paclitaxel for adult patients with
unresectable locally advanced or
metastatic TNBC whose tumors
express PD-L1 (PD-L1–stained,
tumor-infiltrating immune cells of
any intensity covering ≥1% of the
tumor area), as determined by an
FDA-approved test
More to come!
Immune Checkpoint Inhibitors
Under Investigation in TNBC
Anti–PD-1 inhibitors:
Pembrolizumab
Nivolumab
Anti–PD-L1 inhibitors:
Atezolizumab
Durvalumab
Avelumab
Anti–CTLA-4 inhibitors:
Ipilimumab
Tremelimumab
TNBC tumors with a highly invasive
characteristic express a large amount of PD-L1
and a high degree of TILs compared with other
subtypes of breast cancer
Implicates immunogenic nature of TNBC
Rationale for testing/use of immunotherapies
in TNBC
More aggressive forms of breast cancer have some
degree of host immunity, but it appears to decrease
as the tumors progress and become more resistant
(eg, advanced, heavily pretreated TNBC)
Reduction in body’s immune response to the cancer
Immunotherapy may be more effective in earlier
stages of TNBC
Rationale for testing/use of immunotherapies
in neoadjuvant or adjuvant settings
Multimodal therapy may enhance the activity of
immunotherapies in TNBC and other subtypes
of breast cancer
Combination or sequential strategies with
chemotherapies, targeted therapies, other
immunotherapies with nonredundant
mechanisms of action, vaccines, surgery,
radiation, and cryotherapy are being explored

5. Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
SELECTION OF KEY IMMUNO-ONCOLOGY
CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1
PRACTICE AID
Atezolizumab + nab-paclitaxel atezolizumab +
AC surgery atezolizumab
vs
placebo + nab-paclitaxel placebo + AC surgery
NCT03197935 IMpassion031
Phase 3
Anti–PD-L1
Atezolizumab + paclitaxel + carboplatin
atezolizumab + (AC or EC) surgery atezolizumab
vs
placebo + paclitaxel + carboplatin placebo + (AC or EC)
surgery placebo
NCT03281954 GBG 96-GeparDouze
Phase 3
Anti–PD-L1
Atezolizumab + nab-paclitaxel + carboplatin
surgery AC or EC or FEC
vs
nab-paclitaxel + carboplatin surgery AC or EC or FEC
NCT02620280 NeoTRIPaPDL1
Phase 3
Anti–PD-L1
NCT03036488a KEYNOTE-522
Phase 3
Anti–PD-1
Durvalumab durvalumab + nab-paclitaxel
durvalumab + EC surgery
vs
placebo placebo + nab-paclitaxel placebo + EC surgery
NCT02685059 GeparNuevo
Phase 2
Anti–PD-L1
Pembrolizumab + nab-paclitaxel
pembrolizumab + EC surgery
NCT03289819 NIB
Phase 2
Anti–PD-1
Olaparib durvalumab + olaparib surgery
NCT03594396
Phase
1/2
Anti–PD-L1
Pembrolizumab + radiotherapy boost surgery
NCT03366844 Anti–PD-1
Phase
1/2
Nivolumab surgery
vs
nivolumab + doxorubicin surgery
NCT03815890 BELLINI
Phase 2
Anti–PD-1
Nivolumab + ipilimumab
core biopsy/cryoablation surgery nivolumab
vs
surgery
NCT03546686
Phase 2
Anti–PD-1 + anti–CTLA-4
Neoadjuvant Setting
Pembrolizumab + paclitaxel + carboplatin
pembrolizumab + (AC or EC) surgery pembrolizumab
vs
placebo + paclitaxel + carboplatin placebo + (AC or EC)
surgery placebo

6. Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
SELECTION OF KEY IMMUNO-ONCOLOGY
CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1
PRACTICE AID
Pembrolizumab + radiotherapy
vs
observation + radiotherapy
(for residual disease after neoadjuvant chemo and surgery)
NCT02954874 SWOG-S1418
Phase 3
Anti–PD-1
Avelumab
vs
observation
(after surgery, neo- or adjuvant chemo, and radiotherapy if indicated)
NCT02926196 A-Brave
Phase 3
Anti–PD-L1
Atezolizumab + paclitaxel →
atezolizumab + (AC or EC) → atezolizumab
vs
paclitaxel → AC or EC
NCT03498716 IMpassion030
Phase 3
Anti–PD-L1
Nivolumab
vs
capecitabine
vs
nivolumab + capecitabine
(for residual disease after neoadjuvant chemo and surgery)
NCT03487666 OXEL
Phase 2
Anti–PD-1
Adjuvant Setting
Nivolumab + ipilimumab + radiotherapy
vs
capecitabine + radiotherapy
(for residual disease after neoadjuvant chemo and surgery)
NCT03818685
BreastImmune03
Phase 2
Anti–PD-1 + anti–CTLA-4
Atezolizumab + capecitabine
vs
capecitabine
(for residual disease after neoadjuvant chemo and surgery)
NCT03756298
Phase 2
Anti–PD-1

7. Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
SELECTION OF KEY IMMUNO-ONCOLOGY
CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1
PRACTICE AID
Atezolizumab + nab-paclitaxel
vs
placebo + nab-paclitaxel
NCT02425891 IMpassion130
Phase 3
Anti–PD-L1
Atezolizumab + paclitaxel
vs
placebo + paclitaxel
NCT03125902 IMpassion131
Phase 3
Anti–PD-L1
Pembrolizumab + [nab-paclitaxel or
paclitaxel or (gemcitabine + carboplatin)]
vs
placebo + [nab-paclitaxel or paclitaxel or (gemcitabine + carboplatin)]
NCT02819518 KEYNOTE-355
Phase 3
Anti–PD-1
Metastatic/Advanced Setting
Pembrolizumab
NCT02447003 KEYNOTE-086
Phase 2
Anti–PD-1
1st line
1st line
1st line
Durvalumab + tremelimumab → durvalumab
NCT02536794
Phase 2
Anti–PD-L1 + anti–CTLA-4
1st line 1st line
Atezolizumab +
[(gemcitabine + carboplatin) or capecitabine]
vs
placebo + [(gemcitabine + carboplatin) or capecitabine]
NCT03371017 IMpassion132
Phase 3
Anti–PD-L1
1st line
Pembrolizumab
vs
capecitabine or eribulin or gemcitabine or vinorelbine
NCT02555657 KEYNOTE-119
Phase 3
Anti–PD-1
≥2nd line
Pembrolizumab + doxorubicin → pembrolizumab
NCT02648477
Phase 2
Anti–PD-1
Pembrolizumab + nab-paclitaxel
NCT02752685
Phase 2
Anti–PD-1
1st line 1st line
Pembrolizumab + carboplatin + gemcitabine
vs
carboplatin + gemcitabine
NCT02755272
Phase 2
Anti–PD-1
Pembrolizumab + cyclophosphamide
NCT02768701
Phase 2
Anti–PD-1
1st line 1st line

8. a
Continued in adjuvant setting.
1. https://clinicaltrials.gov. November 26, 2019.
AC: doxorubicin + cyclophosphamide; chemo: chemotherapy; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; EC: epirubicin + cyclophosphamide; FEC: fluorouracil + epirubicin + cyclophosphamide; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1.
Access the activity,“On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: Rational Strategies to Make the Most of
Immunotherapies and Other Effective Treatment Modalities Throughout the Disease Continuum,”at PeerView.com/PMD40.
SELECTION OF KEY IMMUNO-ONCOLOGY
CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1
PRACTICE AID
Olaparib → durvalumab + olaparib
NCT03801369
Phase 2
Anti–PD-1
Pembrolizumab + carboplatin + nab-paclitaxel
NCT03121352
Phase 2
Anti–PD-1
Pembrolizumab + radiotherapy
NCT02730130
Phase 2
Anti–PD-1
Metastatic/Advanced Setting (Cont’d)
Nivolumab + romidepsin + cisplatin
NCT02393794
Phase
1/2
Anti–PD-1
1st/2nd line
1st-3rd line
≥2nd line
Pembrolizumab + eribulin mesylate
NCT02513472 ENHANCE-1
Anti–PD-L1
≥1st line 1st-3rd line
Atezolizumab + cobimetinib + paclitaxel
vs
atezolizumab + cobimetinib + nab-paclitaxel
vs
cobimetinib + paclitaxel
vs
placebo + paclitaxel
NCT02322814
Phase 2
Anti–PD-L1
1st line
Pembrolizumab + lenvatinib
NCT03797326 LEAP-005
Phase 2
Anti–PD-1
≥2nd line
Durvalumab + paclitaxel → durvalumab
NCT02628132
Anti–PD-1
≥2nd line
Radiotherapy → nivolumab
vs
doxorubicin → nivolumab
vs
cisplatin → nivolumab
vs
cyclophosphamide → nivolumab
vs
nivolumab
NCT02499367 TONIC
Phase 2
Anti–PD-1
2nd-4th line
Phase
1/2
Phase
1/2