Triple negative breast cancer (TNBC) is an aggressive form of breast cancer defined by a lack of estrogen, progesterone, and HER2 receptors. It accounts for 15-20% of breast cancers and is associated with poorer prognosis and shorter survival. Current treatment options for TNBC include chemotherapy. Immunotherapy with PD-1 inhibitors such as pembrolizumab shows promise based on results from the KEYNOTE-355 trial showing improved progression-free survival compared to chemotherapy alone in patients with TNBC. PARP inhibitors in combination with platinum-based chemotherapy may provide a preferred treatment option for patients with BRCA1/2 mutated TNBC based on clinical trial results and NCCN guidelines.
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TREATMENT OPTIONS FOR TNBC ESMO 2022.pptx
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Treatment of stage iv
Triple negative breast
cancer
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2
(Table of Contents):
A.Breast Cancer Landscape:
-Overview of TNBC
B. Current Treatment of TNBC:
1.PARB INHIBITORS
2.PLATINIUM
3.PD-1 INH (KEYTRUDA):
C. Introduction to KEYTRUDA
-Rationale for I/O in TNBC
- Clinical TriaL (KEYNOTE-355)
- Monitoring for Response
- Take Home Message
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Breast Cancer Is the Leading Cause of Female Cancer
Death Worldwide
1. GLOBOCAN 2020: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2020. Population fact sheet: World (both sexes).
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed January 2021.
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5
Worldwide female incidecne and mortality rates
Globocan 2020
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Breast Cancer Incidence and Mortality Rates
Vary Depending on Location
1. GLOBOCAN 2020: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2020. Population fact sheet: World (both sexes).
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed January 2021.
Region-Specific
Incidence and
Mortality Age-
Standardized Rates for
Female Breast Cancer
in 2020. Rates are
shown in descending
order of the world
(W) age standardized
incidence rate, and
the highest national
age-standardized
rates for incidence
and mortality are
superimposed.
Source: GLOBOCAN
2020.
Globocan 2020
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10
Egypt 2020
(incidence&
mortality
rates)
Globocan 2020
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-FACT:
BREAST CANCER IS
THE MOST COMMON
CANCER AND CENCER -
RELATED DEATH IN
FEMALES
GLOBOCAN, NCI ,NCCN,
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Breast Cancer Is a Heterogeneous Disease
ā¢ Breast cancer is a heterogeneous
disease, comprising a large number
of subtypes with different
morphological features and clinical
behaviors1
ā¢ Gene-expression microarray data
have identified five main breast
cancer subgroups2ā4
ā Luminal A
ā Luminal B
ā Human epidermal growth
factor receptor 2
ā Basal-like/TNBC
ā Normal breast-like
Figure from SĆørlie T, et al. Proc Natl Acad Sci U S A.
2001;98(19):10869ā10874.
1. Tomao F, Papa A, Zaccarelli E, Rossi L, Caruso D, Minozzi M, Vici P, Frati L, Tomao S. Triple-negative breast cancer: new perspectives for targeted therapies. Onco
Targets Ther. 2015 Jan 16;8:177-93.
2. Perou CM, SĆørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, LĆønning
PE, BĆørresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52
3. SĆørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D,
LĆønning PE, BĆørresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001 Sep
11;98(19):10869-74.
4. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, LĆønning PE, Brown PO, BĆørresen-Dale AL,
Botstein D. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23.
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TNBC Is Generally an Aggressive Form of Breast Cancer
With a High Likelihood of Distant Metastases1
ā¢ Triple-negative breast cancer (TNBC) is clinically defined by
the lack of ER, PR, and HER2 expression.
ā¢ TNBC represents approximately 15%ā20% of BC cases
diagnosed worldwide.
ā¢ USUALLY presents With high-grade, ductal invasive carcinoma
being the most common histological subtype. 1
ā¢ TNBC is generally a hard-to-treat, aggressive form of BC,
associated with a worse prognosis, due to :
ā High likelihood of recurrence/distant metastases within 1st
2ā3 years of diagnosis1
ā TNBC is associated with shorter median survival from time
of relapse to death
BC = breast cancer; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor
1-Diana A, Carlino F, Franzese E, Oikonomidou O, Criscitiello C, De Vita F, Ciardiello F, Orditura M. Early Triple-
Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. Cancers (Basel). 2020 Mar
29;12(4):819.
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Triple-Negative Basal-like Breast Cancer Has
Unique Pathologic and Molecular Characteristics1
aMajority across studies.
EGFR = epidermal growth factor receptor; TNBC = triple negative breast cancer.
1-Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast
Cancer. 2009 Jun;9 Suppl 2(Suppl 2): S73-81.
Immunophenotypic Characteristicsa
Pathologic Characteristics
Estrogen receptor negative Grade III
HER2 negative High proliferation rate
P-cadherin negative Nuclear pleomorphism
p63 negative Pushing borders of invasion
HER1 (EGFR) positive Geographic necrosis
Cytokeratin 5/6 positive p53 mutations (ā 80%)
c-Kit positive BRCA1 germline mutations
Vimentin positive Ductal and metaplastic histology
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Basal-like* and TNBC Are Associated With Specific Risk
Factors1
Risk Factors for Basal-like or
TNBCa
African American race
Premenopausal status
Increasing parity
Younger age at first-term
pregnancy
Shorter duration of breast
feeding
Use of lactation-suppression
techniques
Elevated waist-to-hip ratio (both
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Patients With Basal-like Breast Cancer have Poor
Prognosis
Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer. 2009 Jun;9
Suppl 2(Suppl 2):S73-81.
Prognosis of Basal-like Breast
Cancer
in Comparison to Other Subtypes
Luminal A Luminal B Normal Basal HER2
Survival
100
80
60
40
20
24 48 72 96
Time (months)
Probability,
%
P < 0.01
0
0
Recurrence-free Survival
100
80
60
40
20
24 48 72 96
Time (months)
Probability,
% P < 0.01
0
0
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Frontline Basal-like Breast Cancer Is Chemo-Sensitive, but
Has Poor Long-term Survival
BBC = basal-like breast cancer; DDFS = distant disease-free survival; pCR = pathologic complete response.
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple-negative paradox: primary
tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007 Apr 15;13(8):2329-34.
0
Time (months)
6 12 18 24 30 36 42 48 54 60
Distant
disease-free
survival
(%)
0
10
20
30
40
50
60
70
80
90
100
Luminal A
Luminal B
BBC
HER2+
Higher Risk of Relapse in Basal-like Breast
Cancer in
Patients Not Achieving pCR
DDFS in patients with
residual disease after
neoadjuvant
chemotherapy by breast
cancer subtype
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-Specific molecular subtype exhibits
a unique molecular profile and set of
risk factors, aggressive , high grade
ā¦..with early pattern of metastasis
,increased in residual disease and
Associated with shorter survival
after the recurrenceā¦ā¦limited
treatment options and poor
prognosis despite the chemo-
sensitivity nature
-TNBC
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44
THE TNT TRIAL randomized patients with
triple negative breast cancer (TNBC) to receive
treatment with carboplatin OR docetaxel :
In the unselected population, the outcomes were
similar , but in patients with BRCA1/2
mutations, response to carboplatin and
progression free survival (PFS ) were much
improved vs. docetaxel
TNT : CONCLUSION
Clinical care options
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45
āBASED ON THE RESULTS OF
PREVIOUSLY MENTIONED TRIALS FOR
TRIPLE -NEGATIVE
RECURRENT/METASTATIC BREAST
CANCER AND GERMLINE MUTATED
BRCA1/2 ( TNBC ā BRCA1/2 MUTATION) ā¦..
THE NCCN HAS INCLUDED THE ā 2 FDA
APPROVED PARP-INH(OLAPARIB AND
TALAZOPARIB) + PLATINUM ā AS
PREFERED TREATMENT OPTIONS ā
(BRCA 1/2 TNBC)
CLINICAL CARE OPTIONS + NCCN GUIDELIENS + ESMO
GUIDELIENS
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CPS = combined positive score; PD-L1 = programmed death ligand 1; TNBC = triple-negative breast cancer.
Rationale
for I/O in
TNBC
ESMO GUIDELIESN
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TNBC Treatment: Current Landscape1
ā¢ Conventional cytotoxic agents remain the mainstay
treatment for TNBC despite their limited efficacy.1
ā¢ Breast Cancer is generally considered a ānon-
immunogenicā tumor due to its low mutational load
and poor immune infiltrate. However, the TNBC
subtype displays several features, such as the presence
of TILs, the expression of immune evasion molecules in
a tumor microenvironment such as PD-L1, and the
genomic instability and consequently the highest
number of mutations that make it a āhotā and
immunogenic tumor1.
TIL = tumor-infiltrating lymphocyte; TNBC = triple-negative breast cancer.
1-Diana A, Carlino F, Franzese E, Oikonomidou O, Criscitiello C, De Vita F, Ciardiello F, Orditura M. Early Triple-Negative Breast Cancer: Conventional
Treatment and Emerging Therapeutic Landscapes. Cancers (Basel). 2020 Mar 29;12(4):819.
2-Marra A, Viale G, Curigliano G. Recent advances in triple-negative breast cancer: the immunotherapy era. BMC Med. 2019 May 9;17(1):90.
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Escape From Immune Surveillance Is a Hallmark of Cancer
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74.
Therapeutic targeting of the hallmarks of cancer
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Cancer Evades Immune Cell Recognition and Destruction
via Several Mechanisms
APC, antigen-presenting cells; IL, interleukin; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility
complex; Tregs, T-regulatory cells.
Immune evasion or immunosuppressive strategies used by
tumor cells1:
Tumors use numerous strategies to evade immune responses.
A. Cancer cells can downregulate expression of MHC molecules that
present tumor antigens to T-cells, and suppress tumor antigen
presentation by professional APC, thereby avoiding recognition by T-
cells.
B. Tumors create an immunosuppressive environment by recruitment and
retention of suppressive Tregs and MDSCs.
C. By secretion of immune-regulating or suppressive cytokines (IL-4, IL-5,
IL-6, IL-10, and IL-13 and transforming growth factor-beta) and
mediators (prostaglandins, indoleamine 2,3-dioxygenase.
D. Dysregulation of T-cell checkpoint pathways, including expression of
PD-L1 by tumors, sends negative signals to tumor-specific T cells,
causing T cell inactivation.
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Immune Checkpoint Inhibition:
ā¢ immune-checkpoint pathways are the major mechanism of immune resistance
against T cells that are specific for tumor antigens1.
ā¢ PD1 predominantly regulates effector T cell activity within tissue and tumors,
whereas CTLA4 predominantly regulates T cell activation1.
ā¢ APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; LAG-3 = lymphocyte activation gene 3; MHC = major histocompatibility
complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; Treg = T-regulatory cell.
1- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64.
Immune Checkpoints: PD-1 and CTLA-4
TCR
Tumor cell
PD-L2
PD-L1
Antigen
PD-1
AntiāPD-1
cytotoxic T cell
Activated
MHC
Immune checkpoints regulate different components in the evolution of an immune
response
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ā¢ immune-checkpoint pathways are the major mechanism of
immune resistance against T cells that are specific for tumor
antigens1
ā¢ PD-1 receptors are normally expressed on various immune cells,
including inactivated T cells . AND , usually upregulated in breast
cancer tumors1
ā¢ Tumor cells can express the PD-1 ligands,( PD-L1 )and PD-L21
ā¢ PD-L1 and PD-L2 bind to the PD-1 receptors to inhibit the activated T
cells and allow tumor cells to evade the immune
response1
Immune Checkpoint Inhibition: PD-1
Image adapted from Pardoll DM. Nat Rev Cancer. 2012;12(4):252ā264.
MHC = major histocompatibilitycomplex; PD-1 = programmeddeath receptor-1; PD-L1 = programmed death ligand 1;
PD-L2 = programmeddeath ligand 2; TCR = T-cell receptor.
1-PardollDM. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012 Mar 22;12(4):252-64.
TCR
Tumor cell
PD-L2
PD-L1
Antigen
PD-1
AntiāPD-1
cytotoxic T cell
Activated
MHC
.Blockade of the PD-L1/PD-1 pathway reverses exhausted T
cells and restores antitumor function
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PD-1 Receptor Inhibition May Provide More
Complete
Pathway Blockade Than Targeting a Single Ligand
MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand
1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor.
1- McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013 Oct;2(5):662-73.
Figure: Pardoll DM. Nat Rev Cancer. 2012;12:252ā264.
TCR
PD-1 Receptor Inhibition
1
ā¢ PD-1 is a receptor located on T
cells
ā¢ Antibodies directed against the
PD-1 receptor on T cells block the
binding of both PD-L1 and PD-L2
ā¢ Signaling activities of both PD-L1
and PD-L2 are inhibited
PD-L1 Ligand Inhibition
1
ā¢ PD-L1 and PD-L2 are ligands located on
tumor cells
ā¢ Antibodies targeting the PD-L1 ligand on
tumor cells only block the binding of PD-
L1 to the PD-1 receptor
ā¢ Signaling activities of PD-L2 are not
inhibited
Tumor cell
PD-L2
PD-L1
Antigen
PD-1
AntiāPD-1
cytotoxic T cell
Activated
MHC
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-What Would Your Treatment Plan Be for a Patient With Advanced
TNBC Whose Tumors Express PD-L1 (CPS of ā„10)?
CPS = combined positive score; PD-L1 = programmed death ligand 1; TNBC = triple-negative breast cancer.
Rationale
for I/O in
TNBC
-ROLE OF
PEMBROLIZUMAB
(KEYTRUDA ) IN TNBC?
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KEYTRUDA (pembrolizumab) Reactivates the
Antitumor Immune Response1
MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death
ligand 2; TCR = T-cell receptor.
1. KEYTRUDAĀ® (pembrolizumab) injection Jordan PI.
ā¢ KEYTRUDA is a humanized monoclonal antibody that
blocks the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.1
ā¢ KEYTRUDA releases PD-1 pathway-mediated inhibition
of the immune response, including the antitumor
immune response.1
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āKEYNOTE-355: Study Design,
Clinical Data, and Safety Profileā
5
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KEYNOTE-355: Study Design1
ā¢ Multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy of
KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and
carboplatin in patients with locally recurrent unresectable, or metastatic TNBC, regardless
of tumor PD-L1 expression, who had not been previously treated with chemotherapy
Key Inclusion Criteria
ļ§ Age ā„18 years
ļ§ Centrally confirmed TNBC (ASCO-CAP guideline
criteria)
ļ§ ā„1 measurable lesion on RECIST v1.1
ļ§ Tumor sample from a locally recurrent inoperable
or metastatic site
ļ§ Completion of treatment with curative intent ā„6
months before first disease recurrence
ļ§ ECOG PS 0 or 1
ļ§ Adequate organ function
Key Exclusion Criteria
ļ§ Treatment with an investigational agent within 4
weeks before randomization
ļ§ Previous therapy targeting PD-1, PD-L1, PD-L2
agents or an agent directed to another co-inhibitory T-
cell receptor
ļ§ An active autoimmune disease that required
systemic therapy within 2 years of treatment
ļ§ Diagnosis of immunodeficiency or
immunosuppression within the previous week
ļ§ Active CNS metastases or carcinomatous
meningitis
Stratification Factors
ā¢Chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs gemcitabine and
carboplatin)
ā¢Tumor PD-L1 expression (CPS ā„1 vs CPS <1), according to the PD-L1 IHC 22C3 pharmDx kit
ā¢Prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs no)
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KEYNOTE-355: Study Design1 (continued)
aAssessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. AUC = area under the curve;
BICR = blinded independent central review; PD-L1 = programmed death ligand 1; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; TNBC = triple-negative
breast cancer.
ā¢ Multicenter, double-blind, randomized, placebo-controlled trial evaluating the
efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound,
or gemcitabine and carboplatin, in patients with locally recurrent unresectable,
or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been
previously treated with chemotherapy.
ā¢ Response was assessed by imaging every 8 weeks until week 24, then every 9 weeks during the first year, and then
every 12 weeks thereafter on the basis of Response Evaluation Criteria in Advanced Solid Tumors (RECIST) version 1.1
AUC = area under the curve; DOR = duration of response; ORR = objective response rate; PFS = progression-free survival;
RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1.
Treatment with KEYTRUDA
continued until RECIST v1.1a
- defined progression of
disease as determined by
the investigator,
unacceptable toxicity,
Randomized 2:1
N=847
KEYTRUDA
200 mg
on day 1 every 3
weeks
PLACEBO
on day 1 every 3
weeks
+
+
Paclitaxel
(90 mg/m2 on days 1, 8, and 15
every 28 days)
OR
Paclitaxel protein-bound
(100 mg/m2 on days 1, 8, and 15
every 28 days)
OR
Gemcitabine plus carboplatin
(1000 mg/m2 and AUC
2 mg/mL/min respectively on days 1 and 8
every 21 days)
n=566
n=281
Efficacy outcome measuresa
ā¢ Progression-Free Survival
(PFS)
ā¢ Objective Response rate
(ORR)
ā¢ Duration of Response (DOR)
1. Cortes et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally
recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled,
double-blind, phase 3 clinical trial . Lancet 2020; 396: 1817ā28
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KEYNOTE-355: Baseline Patient Characteristics (ITT;
N=847)1
Patient Characteristics
Age, median (range), years 53 (22-85)
ā„65 years of age, % 21
White, % 68
ECOG PS, %
0 60
1 40
Postmenopausal, % 68
PD-L1 expression, %
CPS ā„1 75
CPS ā„10 38
PD-L1 Expression (CPS ā„10) in
KEYNOTE-355
38%of patients had PD-L1 expression
(CPS ā„10) in the KEYNOTE-355
study.
CPS = combined positive score; ECOG = Eastern Cooperative Oncology Group performance status; ITT = intention-to-treat; PD-L1 =
programmed death ligand 1; TNBC = triple-negative breast cancer.
1. FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
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KEYNOTE-355: Progression-Free Survival (PFS) in Patients Whose
Tumors Expressed PD-L1 With a CPS ā„10 1
aHazard ratio based on Cox regression model with Efronās method of tie handling with treatment as a covariate. One-sided P value based on log-rank
test. Both were stratified by chemotherapy on study (taxane vs gemcitabine and carboplatin) and prior treatment with same class of chemotherapy in
the neoadjuvant setting (yes or no).
CI = confidence interval; CPS = combined positive score; gem carbo = gemcitabine and carboplatin; HR = hazard ratio; nab-paclitaxel = paclitaxel protein-
bound; PD-L1 = programmed death ligand 1; Q3W = every 3 weeks; TNBC = triple-negative breast cancer.
1. Cortes et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent
inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3
clinical trial . Lancet 2020; 396: 1817ā28
ā¢ Median PFS was
9.7 (95% Cl, 7.6-
11.3) months with
KEYTRUDA +
paclitaxel, nab-
paclitaxel, or gem
carbo and 5.6(95%
Cl, 5.3-7.5) months
with placebo+
paclitaxel, nab-
paclitaxel, or gem
carbo.
ā¢ The number of
patients with an
event was Grade
ā„3 was 438 (78%)
with KEYTRUDA +
Chemotherapy vs
207 (74%)
Placeboā
chemotherapy.
35%
Reduction in
risk of death
with
KEYTRUDA +
chemotherapy
(nab-paclitaxel;
paclitaxel; or
gemcitabine
plus
carboplatin)
HRa= 0.65 (95% CI, 0.49ā0.86)
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1. Cortes et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally
recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-
blind, phase 3 clinical trial . Lancet 2020; 396: 1817ā28
KEYNOTE-355: Progression-Free Survival (PFS) in Patients Whose
Tumors Expressed PD-L1 With a CPS ā„10 ā Subgroup Analysis 1
LIMITATION:
KEYNOTE-355 was
not powered to
detect differences
in the treatment
effect in the
subgroups;
therefore, results
from these
subgroup analyses
should be
interpreted with
caution.
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KEYNOTE-355: Response Rates in Patients Whose
Tumors Expressed PD-L1 With a CPS ā„10 1
aā+ā denotes ongoing.
CPS = combined positive score; CR = complete response; gem carbo = gemcitabine and carboplatin; nab-paclitaxel = paclitaxel
protein-bound; PD-L1 = programed death ligand 1; PR = partial response.
1. FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
Range 9.9-29.8
(5.3, 15.8)
Median
95% CI
95% CI
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Efficacy Results in Patients Whose Tumors
Expressed PD-L1 With a CPS ā„101
63
End Points
KEYTRUDA +
Paclitaxel, Nab-
paclitaxel, or Gem
Carbo
PLACEBO +
Paclitaxel, Nab-
paclitaxel, or Gem
Carbo
PFS Number of patients with event
(%)
136 (62%) 79 (77%)
Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5)
Hazard ratioa (95% CI) 0.65 (0.49, 0.86)
P valueb 0.0012
ORR Objective confirmed response
rate (95% CI)
53% (46, 60) 40% (30, 50)
Complete response rate 17% 13%
Partial response rate 36% 27%
DOR Range (months) 19.3 (9.9+, 29.8)d 7.3 (5.3, 15.8)d
% with duration ā„6 monthsc 83% 58%
% with duration ā„12 monthsc 56% 39%
ā¢In KEYNOTE-355, when patients with locally recurrent, unresectable or metastatic
TNBC (PD-L1 CPS ā„10) received KEYTRUDA plus chemotherapy (paclitaxel, nab-
paclitaxel, or gem carbo) (n=220), or the same chemotherapy regimens alone
(n=103).
aBased on Cox regression model with Efronās method of tie handling with treatment as a covariate stratified by chemotherapy on study (taxane vs gemcitabine and carboplatin) and prior
treatment with same class of chemotherapy in the neoadjuvant setting (yes vs no). bOne-sided P value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine
and carboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs no). cFrom product-limit (Kaplan-Meier) method for censored data. dā+ā denotes
ongoing.
CI = confidence interval; CPS = combined positive score; DOR = duration of response; gem carbo = gemcitabine and carboplatin; HR = hazard ratio; ORR = objective response
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KEYNOTE-355: Safety Profile
KEYTRUDA 200 mg every
3 weeks with chemotherapy
n=596
Placebo every 3 weeks with
chemotherapy n=281
All
Grades*(%)
Grades 3-4 (%)
All
Grades*(%)
Grades 3-4 (%)
Nausea 44 1.7 47 1.8
Diarrhea 28 1.8 23 1.8
Constipation 28 0.5 27 0.4
Vomiting 26 2.7 22 3.2
Alopecia 34 0.8 35 1.1
Rashā”
26 2 16 0
CoughĀ§
23 0 20 0.4
Decreased
appetite
21 0.8 14 0.4
HeadacheĀ¶
20 0.7 23 0.7
* Graded per NCI CTCAE v4.03
ā Includes fatigue and asthenia
ā” Includes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash,
rash erythematous, eyelid rash
Ā§ Includes cough, productive cough, upper-airway cough syndrome
Ā¶ Includes headache, migraine, tension headache
1. KEYTRUDA Jordan PI
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KEYNOTE-355: Safety Profile1
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
1. KEYTRUDA Jordan PI
(22%)
(14%)
(7%)
(6%)
(5%)
(5%)
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-MOST GRADE 3 WAS HEMATOLGICAL TOXITIES AND ELEVATED LIVER
ENZYMS
-0.4% DEATH: 1 PATIENT DUE TO AKI AND 1 PATIENT DUE TO PENUMONITIS
79. For Internal Use Only
79
Monitoring for Response and
Immune-mediated Adverse Reactions
in Patients Receiving KEYTRUDA
(Pembrolizumab)
80. For Internal Use Only
80
Considerations for Monitoring Response to
KEYTRUDA (Pembrolizumab)1
ļ§ Patients should be treated with KEYTRUDA
(pembrolizumab) until disease progression or
unacceptable toxicity.1
ļ§ Atypical responses (ie, an initial transient increase
in tumor size or small new lesions Within the first
few months followed by tumor shrinkage) have been
observed. ā¦..Clinically stable patients with initial
evidence of disease progression should remain on
treatment until disease progression is confirmed.1
1. KEYTRUDA Jordan PI
81. For Internal Use Only
81
81
INDICATIONS AND USAGE
KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody
indicated:
Triple-Negative Breast Cancer (TNBC)
ļ· for the treatment of patients with high-risk early-stage TNBC in
combination with chemotherapy as neoadjuvant treatment, and then
continued as a single agent as adjuvant treatment after surgery.
ļ· in combination with chemotherapy, for the treatment of patients with
locally recurrent unresectable or metastatic TNBC whose tumors express
PD-L1 [Combined Positive Score (CPS) ā„10] as determined by a validated
test.
DOSAGE AND ADMINISTRATION
ļ· TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks.
Administer KEYTRUDA as an intravenous infusion over 30 minutes.
DOSAGE FORMS AND STRENGTHS Injection: 100 mg/4 mL (25 mg/mL)
solution in a single-dose vial
Selected Safety Information
KEYTRUDAĀ® (pembrolizumab) PI Jordan.
82. For Internal Use Only
82
Current Treatment of TNBC
NCCN Guidelines: Targeted Therapies and
Associated Biomarker Testing for Recurrent or
Metastatic Cancer1
NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesĀ®) for Breast Cancer Version 4.2022.
Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Last Accessed: 24.7.2022
83. For Internal Use Only
83
-NCCN Guidelines Version 4.2022 Invasive Breast Cancer
ADDITIONAL TARGETED THERAPIES AND ASSOCIATED BIOMARKER
TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR
STAGE IV (M1) DISEASE
Biomarkers Associated with FDA-Approved Therapies
Breast Cancer
Subtype
Biomarker Detection FDA-Approved Agents
NCCN
Category
of
Evidence
NCCN
Categor
y of
Prefere
nce
Anya BRCA1 mutation
BRCA2 mutation
Germline sequencing
Olaparib
Talazoparib
Category 1
Category 1
Preferred
HR-positive/
HER2-negativeb PIK3CA activating
mutation
PCR (blood or tissue
block if blood negative),
molecular panel testing
Alpelisib + fulvestrant c
Category 1
Preferred second or
subsequent-line
therapy
TNBC
PD-L1 expression
Threshold for
positivity
combined
positive score ā„10
IHC
Pembrolizumab +
chemotherapy
(albumin-bound
paclitaxel, paclitaxel,or
gemcitabine and
carboplatin)d
Category 1
Preferred first-
line therapy h
Any NTRK fusion FISH, NGS, PCR (tissue
block)
Larotrectinibe
Entrectinibe Category 2A
Useful in certain
circumstances
Any MSI-H/dMMR IHC, PCR (tissue block)
Pembrolizumabd,f
Dostarlimab-gxlyg
Category
2A
Any
TMB-H (ā„10
muts/mb)
NGS Pembrolizumabd,f Category
2A
NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesĀ®) for Breast Cancer Version 4.2022.
Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Last Accessed: 24.7.2022
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85
-Take Home Message1,2
85
Indication1
ā¢KEYTRUDA, in combination
with chemotherapy, is
indicated for the treatment of
patients with locally recurrent
unresectable, or metastatic
triple-negative breast cancer
(TNBC) whose tumors express
PD-L1 (CPS ā„10) as
determined by an FDA-
approved test.
ā¢In KEYNOTE-355:
āTumor PD-L1 expression was
determined using the PD-L1
IHC 22C3 pharmDx kit.
ā38% of patients with
advanced TNBC had PD-L1
expression (CPS ā„10).
PD-L1 Testing2
CPS = combined positive score; FDA = US Food and Drug Administration; IHC = immunohistochemistry; PD-L1 = programmed death ligand 1; TNBC = triple-negative breast cancer.
1. KEYTRUDA Jordan PI
2- FDA Summary of Safety and Effectiveness Data .available @fhttps://www.accessdata.fda.gov/cdrh_docs/pdf15/P150013S020B.pdf
