Targetted therapies gyn oncology

MOLECULAR SIGNALING
PATHWAYS &
IMPLICATIONS IN GYN
ONCOLOGY
Presenter : Dr Shruthi
Shivdas
Moderator : Prof. Dr Pallavi
VR
02/07/2021
KMIO, Bangalore
DR SHRUTHI SHIVDAS

HALLMARKS OF CANCER
Cancers arise because of
genetic & epigenetic
alterations leading to
Molecular events:
 Turning on proto-oncogenes
 Turning off TSG
 Turning off DNA damage
repair (DDR)
 Turning off apoptotic factors
Microenvironment
 Poor antitumor host immune
response
DR SHRUTHI SHIVDAS

CONTENTS
Signaling Pathways
Genetic & Molecular
Aberrations in Gyn
Cancers
Targetting
Strategies
•Oncoprotein pathways
•Tumor Supressor Protein pathways
•DDR pathways
•Apoptotic pathways
•Immune Checkpoint
•Ovarian Cancer
•Endometrial Cancer
•Cervico- Vaginal
•”-Mabs”
•“-Nibs”
•“-Ribs”
•Immunotherapies
Bevacizumab
PARPi
•Trials
•Recommendations
•Sequencing
•Doses & A/E
•“TUMOR AGNOSIS”
•Basket & Umbrella Trials
Immune Check Point Inhibitors
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ONCOGENES Stimulators of cellular
growth
DR SHRUTHI SHIVDAS

CANCER -PROGRESSION
EGF
VEGF Dysfn of EpCAM, Cadherin
MMP
overexpressi
on
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ONCOGENES
NUCLEAR
Myc (Myelocytomatosis)
Jun Fos
Cyclins & CDK
CYTOPLASMIC
Ras (Rat sarcoma)
Raf (Rapidly Activated
Fibrosarcoma)
C-Src ( Cellular Sarcoma)
CELL MEMBRANE R’s
VEGFR
EGFR
PDGFR
Ret
DR SHRUTHI SHIVDAS

VEGF PDGF
EGF TGFβ bFGF Ang
Endothelial cell &
Pericyte
BRAF
MEK
ERK
RAS
PI3K
AKT
mTor
Tumor
Downstr
eam
signaling
cascade
pathway
s
Membrane
Receptors
LiGAND
Nuclear
Transcrip
tion
Factors
DR SHRUTHI SHIVDAS

The PI3K-AKT-mTOR signalling is
involved in multiple cellular processes
including metabolism, motility,
proliferation, growth, and cell survival.
MAPK signalling cascade is involved in the
complex regulation of gene expression,
cell cycle progression, translation, cell
adhesion and migration
SIGNALLING PATHWAYS
ARID1A
mutati
on
MAPK PATHWAY
PI3K/ AKT-mToR Pathway
DR SHRUTHI SHIVDAS

ONCOPROTEIN RECEPTORS
EGF R / ErbB (Erythroblastosis oncogene B)R / Her R
 Includes four receptor tyrosine kinases (ErbB1–4 = Her 1–4)
 Eleven potential growth factor ligands including EGF, , transforming growth factor-
α (TGF-α), heparin-binding EGFlike growth factor (HB-EGF), amphiregulin,
betacellulin, epigen, epiregulin, and neuregulin 1–4.
 Downstream signalling cascades ae :
1. Ras/ Raf / MAPK
2. PI-3K- AKT-mToR
3. phospholipase C-γ (PLCγ)
4. ERK1-2
VEGFR
4 receptors VEGFR 1-4
5 ligands VEGF A-E
VEGFRs stimulate the MAPK pathway
DR SHRUTHI SHIVDAS

Wnt SIGNALING PATHWAY
Normally, Wnt pathway is
inactivated,
the majority of the β-catenin
molecules are combined with
GSK-3β, APC and Axin, which
lead to degradation of β-
catenin via the ubiquitin
pathway.
Activation of the Wnt signaling
pathway by Wnt ligands inhibits
the GSK-3β/APC/Axin complex,
inducing the abnormal
accumulation and translocation of
β-catenin to the nucleus, resulting
in gene transcription
Cellular
proliferati
on &
differentia
tion
Wnt ligands (Wnts) (includes NOTCH prots)
are key signalling proteins in numerous
embryonic and adult stem cell niches
including the intestine, liver, skin, brain,
prostate and breasts.
DR SHRUTHI SHIVDAS

TUMOR SUPRESSOR
GENES
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TSG PRODUCTS
NUCLEAR
Rb
P53
CKI
CYTOPLASMIC
PTEN (Phophatase &
Tensin Homologue) -
PI3 AKT MToR pathway
APC- wnt signalling
pathway
CELL MEMBRANE R’s
TGF- Beta
DR SHRUTHI SHIVDAS

RAS
BRAF
MEK
ERK
Oncogene
proteins
CRAF
PI3K
AKT
mTor
PTEN
CDK
p53
P21
P27
P16
Cyclins
Membrane R
TSG proteins- Nu
TSG proteins-
Cy
TSG ligand
– TGF-B
DR SHRUTHI SHIVDAS

TGF - BETA
TGF-β can downregulate the c-
Myc oncogene levels thereby
counteracting Myc-induced cell
proliferation.
TGF-β can also induce growth
arrest by its inhibitory role on
cyclin-dependent kinases (CDK)
via upregulation of p15 (also
termed as INK4B) and p21
expressions .
In human cancer, TGF-β/SMAD
signaling can have a dual role. In
the early phase of tumor
progression, TGF-β/SMAD plays a
tumor suppressing role, while in
advanced stage , it can promote
tumor cell invasion,
DR SHRUTHI SHIVDAS

NUCLEAR TSG PRODUCTS
GUARDIA
N of
genome
GOVERNO
R of
genome
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TP53 – GUARDIAN OF
GENOME
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DNA DAMAGE
REPAIR
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DNA DAMAGE REPAIR (DDR)
DR SHRUTHI SHIVDAS

ONCOGENE ACTIVATION
TSG & DDR INACTIVATION
Tumour progression involves the inactivation
of TSG (including DDR genes) and the
activation of proto-oncogenes.
 Inactivation of both copies of a TSG / DDR
gene is required for carcinogenesis
(RECESSIVE), while germline deletion or
inactivation of one copy results in an increase
in the risk of cancer and is responsible for
many of the known hereditary cancer
syndromes.
 In contrast, activation of only one copy of a
proto-oncogene is required for carcinogenesis
(DOMINANT). Germline deletion or inactivation
of one copy of a proto-oncogene halves the
risk of activation at this locus. DR SHRUTHI SHIVDAS

KNUDSON’S TWO HIT HYPOTHESIS
- TSG
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APOPTOSIS
EXTRINSIC INTRINSIC
The left side
shows the
extrinsic
apoptotic
signaling
pathway, and
the right side
shows the
intrinsic
apoptotic
signaling
pathway.
These pathways
converge at the
activation of
caspases.
Intracellular
Three major specific cell
death receptor/ligand
pairs have been
described, all members
of the Tumor Necrosis
Factor Receptor
Superfamily (TNFRSF):
(1) Fas and Fas
ligand (FasL)
(2) “death
receptors” (DR4
and DR5) and
TNF-related
apoptosis
inducing ligand
(TRAIL)
(3) TNFα and the
TNF receptor DR SHRUTHI SHIVDAS

APOPTOSIS
ACTIVATION
DR SHRUTHI SHIVDAS

APOPTOSIS
INHIBITION
Many cancers show
excessive apoptotic
blockade pathways.
Cancer therapeutics are
under trial targeting TRAIL
ligands and receptors to
stimulate apoptosis; and to
neutralize Bcl2
DR SHRUTHI SHIVDAS

TUMOUR
MICROENVIRONMENT
Immune check point
DR SHRUTHI SHIVDAS

THE IMMUNE CHECKPOINT
Tumor antigens are presented to T-cells by APCs
via the interaction of the MHC and the T-cell
receptors, representing the primary signal for
activating T-cells. (Cognitive phase)
Later on, there is direct interaction between Tcell
and tumor cell (effector phase)
Several negative modulators downregulate the
activity of T-cells, as a part of self- tolerance
• The CTLA-4 is induced in T-cells at the
time of their initial response to antigen; it
binds to B7 with greater affinity than
CD28, resulting in specific T-cell
inactivation.(cognitive phase)
• The PD-1/PD1-L1 pathway – Later
inflammatory signals from continuous
Tcell activation in the tissue induce the
expression of PD1-L1s on tumor cells.
This mechanism is also exploited by tumor cells
to evade the immune system response.
Interaction between B7 on
APCs and CD28 on T-cells
is needed to complete T-cell
activation and expansion.
B7 (APC) – CTLA4 binding in cognitive
phase T cell resopnse and PDL1 (tumor
cell) – PD1 (Tcell) binding in effector DR SHRUTHI SHIVDAS

GENETIC/MOLECULAR
ABNORMALITIES IN GYN
CANCERS DR SHRUTHI SHIVDAS

DDR MUTATIONS IN EOC
DR SHRUTHI SHIVDAS

MOLECULA
R &
GENETIC
DERANGEM
ENTS IN
EOC
CCNE1 – Cyclin E1
DR SHRUTHI SHIVDAS

TP53 SOMATIC MUTATIONS IN EOC
DR SHRUTHI SHIVDAS

GENE ABNORMALITIES IN
ENDOMETRIAL CANCER -
BOKHMAN
DR SHRUTHI SHIVDAS

GENE ABNORMALITIES IN
ENDOMETRIAL CANCER - TCGA
DR SHRUTHI SHIVDAS

MOLECULAR PATHWAYS IN
CERVICAL CACNER
DP-RB-like-E2F4-MuvB complex.
Inhibition
of a
apoptosis
UNCONTROLLED
PROLIFERATION
DR SHRUTHI SHIVDAS

OTHERS…
Germline FOX L2 mutations in Gr Cell Trs
Germline DICER 1 mutations in SCST
Germline SKT11/ LKB1 gene mutations in PJ syndrome
Sporadic mutations in ESS (
 JAZF1/SUZ12 (Juxtaposed with Another Zinc Finger Protein1/Suppressor of Zeste-
12) in Low grade ESS
 YWHAE/NUTM2A/B in HG ESS
DR SHRUTHI SHIVDAS

TARGETTED THERAPIES
Mab
SMI-”nibs, “ribs”
Tumor agnostic therapies
Immune checkpoint
Inhibitors
GeneTherapy
DR SHRUTHI SHIVDAS

DEFINITION
Targeted therapies are therapies targetting signaling molecules that
are more active in cancer cells than in normal cells, critical for cancer
cell growth and metastasis.
The definitions of the terms, biologics, targeted therapy, and immune
therapy overlap.
Target molecules may be molecules critical for proliferation and
invasion of cancer cells.- conventional definition.
Target molecules may also be molecules in the immune system which
help eliminate cancer cells. In this sense, immune therapy is a
subcategory of targeted therapies.
Targetted therapy can be through in-vivo or ex-vivo genetic
modifications . So, gene therapy is also a subcategory.
All pharmacologic means of targeted therapies, that is, small
molecules and antibodies, can be considered biologics.
Berek And Hacker, 7th ed
DR SHRUTHI SHIVDAS

TARGETED THERAPY: A DEFINITION
By targeting differentially expressed and active molecules
unique to cancer cells, targeted therapies affect cancer
cells more than normal cells.
DR SHRUTHI SHIVDAS
A “smart” bomb versus a “cluster”
bomb.

CONTENTS
•-Mabs
•-Nibs / TKI
Target Proliferation & cellular
processes& angiogenesis
•-Ribs
Target DNA Repair Pathways
•Immunotherapi
es
•Gene Therapy
Target Tumour Microenvironment
DR SHRUTHI SHIVDAS

DRUGS TARGETING
PROLIFERATION & CELLULAR
PROCESSES& ANGIOGENESIS
-Mabs
-Nibs
DR SHRUTHI SHIVDAS

TARGETTING STRATEGIES
Block the Receptor
 Growth factor or Angiogenic factor transmembrane
receptor blocking
MONOCOLONAL ANTIBODIES
“-Mabs”
 Large molecules ; donot cross membrane
 Act on the exxtracellular ligand / its receptor on
membrane
 Usually given IV
Block the signal transduction pathways
SMALL MOLECULE INHIBITORS / TYROSINE KKINASE INH
“-Nibs”
 Small molecules; cross membrane & bind to intracellular
proteins
 Gnerally oral DR SHRUTHI SHIVDAS

TK TK TK
Targetting Strategies
+ - -
TK inh on IC domain
of R
“-nibs”
Anti- R mAbs
“-mab”
Anti-ligand
mAbs
“-mab”
ATP
TKI on signalling pathways
“-mibs”
Replication
Trancsription
Proliferation
Angiogenesis
DR SHRUTHI SHIVDAS

INHIBITORS OF EGFR/VEGFR
PATHWAYS (-MABS & -IBS)
“-Mabs”
“-nibs”
DR SHRUTHI SHIVDAS
Melanoma
Endo Ca
LGSOC

1. DSB Repar – Platinum
agents in HRd
2. SSB Repair – PARP-i
TARGETING THE DNA REPAIR
MECHANISM DR SHRUTHI SHIVDAS

TARGETTING THE DSB REPAIR IN
HRd TUMOURS
• Platinum drugs in HRd
Platinum agents are considered as targeted therapy in BRCA mutant cancers as they intercalate
in DNA and cause SSB during replication, which will accumulate into DSB… not corrected in
absence of BRCA.
DR SHRUTHI SHIVDAS

SMALL MOLECULE INHIBITORS OF
SSB REPAIR
- PARP INHIBITORS – “RIBS”
Using PARP-inhibitors
(PARP-i), PARP
enzymes cannot
autoPARylate; thus,
the PARP enzymes
remain bound to the
site of DNA damage
and are trapped (PARP
trapping).
Continued
autoPARylation results
in destabilization of
the PARP/DNA
complex and
eventually the
dissociation of
PARP from the DNA.
This process allows
the DNA repair
proteins, BER, and
NER, to bind to the
DNA damage site.
DR SHRUTHI SHIVDAS

PARPi & HRd
Survival
Normal cell
Repair by HR
PARP detects SSB and aids in repair
During the replication process,
unrepaired SSBs are converted into DSBs
Replicating cells
PARP
Cancer cell with HRD
Only error prone
repair by NHEJ
Cell death
Tumor-specific
killing by PARP
inhibitors
Slide credit: clinicaloptions.com
PARP inhibitor
O’Connor. Mol Cell. 2015;60:547.
Trapped PARP on
single-strand breaks
PARP
DR SHRUTHI SHIVDAS

SMALL MOLECULE INHIBITORS OF
SSB REPAIR
“-RIBS”
DR SHRUTHI SHIVDAS

TARGETTED THERAPIES
RECOMMENDED IN GYNEC
CANCERS DR SHRUTHI SHIVDAS
Bevacizumab
PARPi
ICI

IMPLICATION OF TARGETED
THERAPY IN EOC
DR SHRUTHI SHIVDAS

1960
Cyclophosphamide (1959)
Melphalan
(1964)
Etoposide
(1983)
Carboplatin
(1989)
Altretamine
(1990)
Docetaxel
(1996)
Topotecan
ROC (1996)
PLD-Accelerated
ROC (1999)
PLD-Full
ROC (2005)
Gemcitabine/Carboplatin
PlSOC (2006)
Olaparib
gBRCAmut ROC (2014)
Chemo + Bevacizumab (2014)
PlROC
Rucaparib gBRCAmut/
sBRCAmut ROC (2016)
Chemo + Bevacizumab
PlSOC (2016)
Olaparib
Maintenance PlSOC (2017)
Niraparib
Pembrolizumab
MSI/dMMR ROC (2017)
Cisplatin
(1978)
Paclitaxel
Full (1998)
Paclitaxel
Accelerated
(1992)
Rucaparib
Bevacizumab
1L + Maintenance (2018)
1970 1980 1990 2000 2010 2020
Olaparib
gBRCAmut 1L
Maintenance (2018)
Niraparib
1L Maintenance
(2020)
Niraparib
HRD+ ROC (2019)
Olaparib +
Bevacizumab
HRD+ 1L
Maintenance (2020)
From 2014 to 2020, there have
been 13 new FDA-approved
indications for ovarian cancer;
9 are for PARP inhibitors and 3
are for bevacizumab-
containing regimens for first-
line treatment and treatment of
recurrent disease (both
platinum resistant and
sensitive).
DR SHRUTHI SHIVDAS

TRIALS ON BEVACIZUMAB
ADJUVANT &
MAINTENANCE
GOG218
ICON7
WITH NACT
ANTHALYA
GEICO 1203/NOVA
(Both small Ph2 trials)
RECURRENT
OCEANS
GOG213
AURELIA
CREDITS : DR RAJATHARANGINI DR SHRUTHI SHIVDAS

BEVACIZUMAB – Ist LINE ADJUVANT
SETTING
TRIAL Eligibili
ty
ARMS PFS BENFIFIT OS BENEFIT HR GROUP
IDENTIFIED
ICON7
N=152
8
IIb-IV
Early
stage
G3/CC
C
CP vs CP+B-B
7.5mg/kg
18 cycles total /
until disease
progression
3 months
overall
group
5 mo HR
subgroup
9 mo in HR
subgroup
ALONE
FIGO III
>1cm RD
FIGO IV
GOG
218
N=187
3
III/IV CP vs CP + B
Vs CP+B-
15mg/kg
22 cycles /until
disease
progression/
unacceptable
toxicity
4 mo
benefit in
Arm C alone
(more in HR
)
Benefit in
HR group
alone
FIGO IV &
Ascites
(2 diff
unplanned
Post HOCs )
•In both studies, PFS curves converged a few months after bevacizumab was discontinued,
suggesting that antiangiogenic treatment delays, but does not prevent, disease progression.
•No good biologic markers to identify which patients are most likely to benefit
from bevacizumab into the first-line setting. Ascites known to be associated with high VEGF
expression. Angiogenesis phenotype – MVD (MicroVessel Density)/ CD31 and VEGF-a may
predict response CREDITS : DR RAJATHARANGINI DR SHRUTHI SHIVDAS
Randall et al, 2013
Ferriss et al, 2015

DR SHRUTHI SHIVDAS
 The FDA-approved indication for maintenance bevacizumab is limited to patients
with stage III–IV disease, whereas the NCCN Guidelines include this as an option for

BEVACIZUMAB – DOSES
RECOMMENDED IN FIRST LINE
DR SHRUTHI SHIVDAS

BEVAC – NACT SETTING
CREDITS ; DR RAJATHARANGINI SHRUTHI SHIVDAS
Both studies showed similar safety profiles, no increase in toxicity (≥grade 3
hematological, gastrointestinal and vascular AEs) compared with carboplatin/paclitaxel
therapy .
The serious adverse event rate in BCP- treated patients (25%) was comparable to the
EORTC study (29%) .
• Bevacizumab in the neoadjuvant setting can be considered, although additional
improvement in efficacy is not proven with level I evidence.
ESMO-ESGO 2019 Level of evidence: II Strength of Recommendation: B
• Bevacizumab can be safely administered in the neoadjuvant setting before and after IDS
providing the interval between surgery and administration is at least 4–6 weeks, due to
potential interference with postoperative healing
ANTHALYA trial
complete resection rate was
significantly higher (58.6% vs
45%)
GEICO 1205/NOVA trial
Enhanced rate of surgical
feasibility (88% vs 66%)
& optimality (86 vs 77%)

BEVACIZUMAB - NACT
DR SHRUTHI SHIVDAS

BEVACIZUMAB IN
RECURRENCE..
CREDITS : DR RAJATHARANGINI DR SHRUTHI SHIVDAS
3-4 month PFS benefit
No OS beneifit
3 mo PFS benefit.
No OS benefit, except in weekly paclitaxel group
 mOS – 13 months for weekly paclitaxel
 mOS – 22 months for weekly paclitaxel + Bevacizumab
carboplatin/PLD/bevacizumab is the new
standard regimen for patients with
recurrent PSROC.

BEVACIZUMAB – FDA INDICATIONS
IN EOC
Targe
t
Drug Approv
al year
Indication
VEGFi
Bevacizuma
b (Avastin,
Genentech)
2014 CC
Persistent, recurrent, or metastatic disease GOG
240
2014
OC
Platinum-resistant recurrent, and received no
more than 2 prior chemotherapy regimens
AURELIA
Platinum-sensitive recurrent OCEANS; GOG 213
2016
2018
Advanced (FIGO stage III–IV) EOC’s ICON7; GOG
218
 The FDA-approved indication for 1st line maintenance bevacizumab is limited to patients with stage
III–IV disease, whereas the NCCN Guidelines include this as an option for stage II disease
 The FDA-approved indication for 1st line maintenance bevacizumab is not qualified based on
BRCA1/2 mutation status. In contrast, the NCCN Guidelines single-agent bevacizumab maintenance
is limited to those without a BRCA1/2 mutation
 Bevac alone may not benefit BRCA mutated / HRR mutated pt (extended analysis of GOG 218)
DR SHRUTHI SHIVDAS

BEVACIZUMAB
34,000/-
DR SHRUTHI SHIVDAS
100 mg (4 ml) and 400 mg (16ml) single-dose vials
Withdraw necessary amount of drug and dilute in a total
volume of 100 mL of 0.9% Sodium Chloride Injection.
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.
First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer second infusion over 60
minutes if first infusion is tolerated. Administer all subsequent
infusions over 30 minutes if second infusion over 60 minutes is
tolerated.

BEVACIZUMAB DOSING - FDA
Patients should continue treatment until disease progression or unacceptable toxicity in PSOC/PROC
and CC.
total of up to 22 cycles or until
disease progression, whichever
occurs earlier.
Not more
than 2
lines
chemo
Incomplete St III & all stage 4
DR SHRUTHI SHIVDAS

A/E - BEVACIZUMAB
Across studies, the most
common adverse
reactions observed in
Bevacizumab patients at
a rate >10% were:
Headache; Rhinitis
HYPERTENSION – 35-40%
Severe Hypertension- 18%
Taste alteration/dysguesia
Diarrhoea – 35%
Neutropenia – 37%
Thrombocytpopenia
CVA-11%
CCF – 11%
Fatigue – 10%
Dry skin
Hemorrhage; Epistaxis
Back pain
Exfoliative dermatitis
Across all studies, Bevac
was discontinued in 8%
to 22% of patients
because of adverse
reactions
•DVT – 9%
•Albuminuria – 7%
•Reactions – 2%
Perforation – 2%
DR SHRUTHI SHIVDAS

SERIOUS AE - BEVACIZUMAB
 Gastrointestinal (GI) perforation ranged from 0.3% to 3% of patients across clinical studies
 Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer). Fistula (any grade) occurred in 15% of
patients in the bevacizumab group in GOG 240 (G3/4 – 3%).
 Arterial thromboembolic events (Grade ≥3, 5%, highest in patients with GBM)
 Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
 Congestive heart failure (CHF): Grade ≥3 left ventricular dysfunction (1%)
 Hemorrhage (Grade 3–5) ranged from 0.4% to 7% of patients across clinical studies
 Renal injury and proteinuria
 Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
 Nephrotic syndrome (<1%)
Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel
involvement on CT scan or clinical symptoms of bowel obstruction
The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Bevac-
treated patients; Surgery to be delayed upto4-6 weeks after bevacizumab.
DR SHRUTHI SHIVDAS

PAOLA1-A/E- BEVAC +OLAPARIB
DR SHRUTHI SHIVDAS

Adverse reaction Severity Dosage modification
Thromboembolic Events
•Arterial thromboembolism,
severe
Discontinue Avastin
•Venous thromboembolism,
Grade 4
Discontinue Avastin
Hypertension
•Hypertensive crisis
•Hypertensive encephalopathy
Discontinue Avastin
•Hypertension, severe(SBP
>=180; DBP>=110)
Withhold Avastin till control
Posterior Reversible
Encephalopathy Syndrome (PRES)
Any Discontinue Avastin
Renal Toxicity and Proteinuria
•Nephrotic syndrome Discontinue Avastin
•Proteinuria greater than or equal
to 2 grams per 24 hours in
absence of nephrotic syndrome
Withhold Avastin until proteinuria
less than 2 grams per 24 hours
Infusion-Related Reaction
•Severe Discontinue Avastin
•Clinically significant
Interrupt infusion; resume at a
decreased rate of infusion after
symptoms resolve
•Mild, clinically insignificant Decrease infusion rate
Congestive Heart Failure Any Discontinue Avastin
No dose reductions for Avastin are recommended. DR SHRUTHI SHIVDAS

BEVACIZUMAB
Adverse reaction Severity Dosage modification
Gastrointestinal Perforation
and Fistulae
•GI perforation, any grade
•Tracheoesophageal fistula, any
grade
•Fistula, Grade 4
•Fistula formation involving any
internal organ
Discontinue Avastin
Wound Healing
Complications
Any
Withhold Avastin until adequate wound
healing.
•Necrotizing fasciitis Discontinue Avastin
Hemorrhage
•Grade 3 or 4 Discontinue Avastin
•Recent history of hemoptysis of
1/2 teaspoon (2.5 mL) or more
Withhold Avastin
No dose reductions for Avastin are recommended.
DR SHRUTHI SHIVDAS

ANTIANGIOGENSIS IN EOC
DR SHRUTHI SHIVDAS

ONGOING UNMET NEEDS…
DR SHRUTHI SHIVDAS

PARP INHIBITORS (PARPI) IN
EOC
N o t e : a l l t r i a l s h a v e P F S a s p r i m a r y o b j e c t i v e
1. Frontline
2. Relapsed Ov Ca (ROC)
1. Maintenance
2. Monotherapy
DR SHRUTHI SHIVDAS
1. OlAPARIB
2. Niraparib
3. Rucaparib
4. veliparib
Note : all trials have PFS as primary objective

MAINTENANCE THERAPY WITH PARP INHIBITORS IN FRONTLINE
SETTINGS
RCT STAGE HIGHLIGHT CONCLUSION
SOLO 1
Olaparib
300mg BD
Stage III/IV
HGSOC /
HGEOC
sBRCA /
gBRCA
Median F/U 41m
Median PFS –not
reached in PARP group
(Control group-13.8)
HR-0.3
A statistically significant 70% reduction in the risk of disease
progression or death was seen for olaparib versus placebo (HR
0.30; p < 0.0001),
progression free 3 years from randomization, 60.4% versus 26.9%
PRIMA
Niraparib
300mg OD for
36 months
Suboptimal
Stage III /IV
high risk of
relapse
HGSOC
regardless of
BRCA/ RD
PARP inhib
Median PFS
Placebo Median
PFS
HR
Overall pop 13.8 8.2 0.62
BRCA mutant(30%) 22.1 10.9 0.40
Non BRCA, HRD+(50%) 19.6 8.2 0.50
HR proficient 8.1 5.4 0.68
VELIA
Veliparib
150+CT/ M-
300/400 mg
BD
HGSOC
regardless of
BRCA
Overall pop 23.5 17.3 0.68
BRCA mutant 34.7 22 0.44
HRD+ 31.9 20.5 0.57
Higher incidence of anemia and thrombocytopenia
DR SHRUTHI SHIVDAS
 SOLO1 : 70% reduction in risk of death/ replase with olaparib in BRCAmut
 PRIMA : 57% reduction in risk of relapse or death with niraparib in HRd
Therefore , it would be unfair NOT to use PARPi in firstline in BRCA mut/ HRd
P
A
R
P
i
i
n
P
R
I
M
A
R
Y
S
E
T
T
I
N
G

BEVACIZUMAB + PARPI (MAINTENANCE) IN FRONTLINE SETTINGS
DR SHRUTHI SHIVDAS
RCT STAGE HIGHLIGHT
POALA1
Post chemo maintenance
with Olaparib + Bevac
Vs
Bevac + placebo in pts who
received Bevac with adjuvant
(* 15 month)
Stage III
/IV
HGSOC
regardless
of
BRCA/HRd
PARPi
median PFS
Placebo
median PFS
HR
Overall pop 22.1 16.6 0.5
BRCA mutant
(29%)
37.2 21.7 0.31
HRD + (34%) 28.1 16.6 0.43
HRD neg/ nk
(18%)
16.9 16 0.92
HTN(19%); anemia(17%),neutropenia (6%),fatigue (5%)
Similar to
SOLO1
 Combination beneficial ONLY in BRCA mut / non BRCA HRd.
 PARPi _ Bevac NOT recommended for HRp
Does bevac have any role in the benefit observed in PAOLA1 trial or was it purely due to
olaparib?
• No direct evidence
• Combined analysis of SOLO1, PAOLA1 and GOG 218 showed that addition of Bevac to
olaparib may have a small benefit over single agent olaparib maintenance, restricted to
HRd population
Similar to PRIMA

DR SHRUTHI SHIVDAS
NIRAPARIB MAY
be given in BRCA
unknown / wt
All patients who are BRCA mut/HRd SHOULD be offered
PARPi.
OLAPARIB ONLY in BRCA mut in first line maintenance.
Olaparib MAY BE USED IN BRCA wt along with Bevac,
ONLY if HRd.
Niraparib can be used IRRESPECTIVE of BRCA / HR
status.
Bevac alone studies were not based on BRCA / HRd
status.
In HRp pts, both Niraparib & Bevac provide the same
benefit , which is still sig more than CT alone.
No studies of Rucaparib in Ist line setting

FDA-APPROVED PARP INHIBITORS:
CURRENT INDICATIONS IN OVARIAN CANCER –
FIRST LINE
DR SHRUTHI SHIVDAS
Olaparib Niraparib Rucaparib
FIRST LINE : ADJUVANT + MAINTENANCE
 First-line maintenance therapy for
BRCA-mutated advanced ovarian cancer
in CR/PR to platinum-based CT (SOLO1)
 First-line maintenance therapy in combination
with bevacizumab for HRd ovarian cancer in
CR/PR to platinum-based CT
(PAOLA1)
advanced ovarian cancer in CR/PR to
platinum-based CT regardless of BRCA
mutation status
REGARDLESS of
BRCA / HR status

INTEGRATING TARGETTED
THERAPY FIRST LINE
SETTING IN EOC DR SHRUTHI SHIVDAS

TESTING
First, every patient should receive germline testing, ideally a panel,
because there are more than 30 hereditary breast and ovarian cancer
genes that are important.
If no germline BRCA mutation is identified, the tumor should undergo HRD
testing.
Of note, it is not optimal to start with an HRD test as it will miss many
DR SHRUTHI SHIVDAS

BEVAC /
PARPI IN
FIRST
LINE
DR SHRUTHI SHIVDAS

DR SHRUTHI SHIVDAS
ASCO – HGSOC /HGEOC
NCCN- Stag II-IV type1/2 EOC
E
 NO ROLE IN STAGE ½
 Olaparib ONLY in BRCA
mut in Ist line.
 Olaparib MAY BE USED IN
BRCA wt / HRd along with
Bevac
 Niraparib can be used
IRRESPECTIVE of BRCA /
HR status.
 Bevac alone studies were
not based on BRCA / HRd
status
FDA – FIRST LINE

INTEGRATED MAINTENANCE TREATMENT PARADIGM
FOR
FIRST-LINE ADVANCED EOC (2020)
IV Q3W carboplatin
+ paclitaxel
No bevacizumab
BRCA mutant
HRD:[1,2]
Add PARPi (preferred)
Nira / Ola
HRP:
Add PARPi (Nir)- preferred
as some may respond
exceptionally
or
Observation
Bevacizumab during
chemotherapy and
in maintenance
BRCA mutant
HRD[3]:
Add PARPi (preferred)
Ola
HRP[4,5]:
Continue bevacizumab
Decision #1
NACT vs
Primary debulking
Decision #2
Bevacizumab Y/N
Decision #3
Add PARPi?
SOLO-1
PRIMA
PRIMA
PAOLA-1
GOG 218
STEP1: Testing
- Germline panel
testing (all EOC)
- Tumor HRD
testing (if germline
BRCAwt)
1. Moore. NEJM. 2018;379:2495. 2. Gonzalez-Martin. NEJM. 2019;381:2391. 3. Ray-Coquard. NEJM.
2019;381:2416.
4. Burger. NEJM. 2011;365:2473. 5. Chan. NEJM. 2016;374:738.
85% to 90% of the patients will receive
bevacizumab, including the settings of stage
IV, neoadjuvant, and residual disease with
primary debulking.
TEST
for
HRD
if not
teste
d
DR SHRUTHI SHIVDAS

OLAPARIB vs NIRAPARIB in BRCAmut
BEVAC - naive
In the BRCA-mutated ovarian cancer patient population, clinicians must
decide whether to use olaparib as in SOLO-1 (assuming bevacizumab is not
an option) or niraparib, as in PRIMA.
With the usual caveats regarding cross-trial comparisons, when looking at
SOLO-1 and PRIMA, niraparib may be more effective in the BRCA1-mutated
subset of patients, and preferable.
BRCA1-mutated ovarian cancer is approximately 3 times more common
thanBRCA2-mutated ovarian cancer and more difficult to treat; less
responsive to PARPi than BRCA2mut.
DR SHRUTHI SHIVDAS

HR PROFICIENT – NIRAPARIB VS
BEVACIZUMAB
In patients with HR-proficient disease, the potential risk of PARP-
inhibitor therapy may outweigh the modest benefit.
In this situation, bevacizumab-containing regimens upfront may be
considered, with the option to administer a PARP inhibitor in later
lines; however, this approach will need to demonstrate a subsequent
response to platinum in these poor-prognosis patients.
On the other hand, bevacizumab could be postponed to the second
line based on data for patients with platinum-sensitive and platinum-
resistant relapse.
DR SHRUTHI SHIVDAS

FIRST LINE EOC
DR SHRUTHI SHIVDAS
FDA NCCN
SINGLE AGENT
BEVACIZUMAB
MAINTENANCE
Only Stage 3 and stge4 Stages II - IV
Single agent bevac
maintenance NOT decided
by BRCA mut status
Single agent bevac restricted to
patients WITHOUT BRCA mut (GOG
218)
 NCCN removed single-agent bevacizumab as a maintenance therapy option for BRCAmut pts
in CR/PR after platinum + Becvac firstline.
70% reduction in relapse, with bevacizumab + olaparib maintenance vs bevac maintenance alone
exploratory analysis of GOG-0218 based on BRCA mutation status suggests that bevacizumab may not improve PFS
in patients with BRCA1/2 mutations
MAINTENANCE OLAPARIB +
BEVACIZUMAB
Ola + Bevac restricted to
HRd / BRCA mut , based on
POALA1
No such restriction in BRCA wt, can
be given without HRD testing
NIRAPARIB MAINTENANE
POST BEVACIZUMAB WITH
CHEMO
Niraparib maintenance not
influenced by BRCA mut
status or whether bevac was
If patient has received bevac with
first line CT, Niraparib maintenance
restricted to those with BRCA mut

NCCN – FIRST LINE OPTIONS
DR SHRUTHI SHIVDAS
No bevac

DR SHRUTHI SHIVDAS
ASCO – HGSOC /HGEOC
NCCN- Stag II-IV type1/2 EOC
E
 NO ROLE IN STAGE ½
 Olaparib ONLY in BRCA
mut in Ist line.
 Olaparib MAY BE USED IN
BRCA wt / HRd along with
Bevac
 Niraparib can be used
IRRESPECTIVE of BRCA /
HR status.
 Bevac alone studies were
not based on BRCA / HRd
status.
 Veliparib / Ruca parib not
recommended in first line
FDA – FIRST LINE

PARP INHIBITORS IN
RECURRENT OVARIAN
CANCER
NIRAPARIB
NOVA/ENGOT OV16 -
maintenance
QUADRA – ph2
monotherapy
OLAPARIB
Maintenance
STUDY19 – ph2
SOLO2/ENGOTOV21
MONOTHERAPY
STUDY42- ph2
SOLO3 – ph3
RUCAPARIB
Maintenance
ARIEL 3 – Ph3
Study 10 – ph2
monotherapy
ARIEL2 – Ph 2
CREDIT : DR RAJATHARANGINI DR SHRUTHI SHIVDAS

PIVOTAL STUDIES OF PARPi IN PSROC
(MAINTENANCE AFTER CHEMO)
Study Study 19[1] SOLO-2[2]
gBRCAm
NOVA[3]
gBRCAm
NOVA[3]
Non-gBRCAm
ARIEL-3[4]
BRCAm
ARIEL-3[4]
ITT
Agent/comparator Olaparib vs placebo Niraparib vs placebo Rucaparib vs placebo
Median PFS, mos 8.4 vs 4.8 19.1 vs 5.5 21.0 vs 5.5 8.7 vs 4.3 16.6 vs 5.4 10.8 vs 5.4
PFS HR
(investigator
assessed)
0.35
(95% CI:
0.25-0.49;
P < .001)
0.30
(95% CI:
0.22-0.41;
P < .0001)
0.27
(95% CI:
0.18-0.40)
0.53
(95% CI:
0.41-0.68)
0.23
(95% CI:
0.16-0.34,
P < .0001)
0.36
(95% CI:
0.30-0.45;
P < .0001)
PFS HR
(BICR)
0.39
(95% CI:
0.27-0.55;
P < .001)
0.25
(95% CI:
0.18-0.35;
P < .0001)
0.27
(95% CI:
0.17-0.41;
P < .0001)
0.45
(95% CI:
0.34- 0.61;
P < .0001)
0.20
(95% CI:
0.13-0.32;
P < .0001)
0.35
(95% CI:
0.28-0.45;
P < .0001)
1. Ledermann. NEJM. 2012;366:1382. 2. Pujade-Lauraine. Lancet Oncol. 2017;18:1274.
3. Fabbro. Gynecol Oncol. 2019;152:560. 4. Coleman. Lancet. 2017;390:1949.
The NOVA study is the only clinical trial of a PARP inhibitor to evaluate efficacy in the
germline BRCA–mutant and difficult-to-treat non-germline BRCA patient populations.
DR SHRUTHI SHIVDAS

CURRENT INDICATIONS IN OVARIAN CANCER
the gain is greatest in those with a BRCA1/2 mutation >non BRCA HRd > no HRd
DR SHRUTHI SHIVDAS
(PAOLA1)
mutation status
MAINTENANCE IN RECURRENT SETING
 Maintenance therapy for recurrent ovarian
cancer in CR/PR to platinum-based CT regardless
of BRCA mutation status
 Maintenance therapy for recurrent
ovarian cancer in CR/PR to platinum-
based CT regardless of BRCA mutation
status
 Maintenance therapy for
recurrent ovarian cancer in CR/PR
to platinum-based CT regardless
REGARDLESS of
BRCA / HR status

PARP I MONOTHERAPY IN
REUCRRENCE
DR SHRUTHI SHIVDAS
MONOTHERAPY
SOLO3
Ph2
Olaparib
monotherapy
vs non
platinum
chemo in
gBRCA PSROC
(HGSOC /
HGEOC) with
>= 2prior lines
of CT
improvements in
ORR and PFS
compared with
QUADRA
Ph2
Niraparib in
heavily pre-
treated PSROC
HRd .
ORR of 28%
ARIEL 2 Part1
Ph2
Rucaparib
monotherapy
in PSROC
associated
with significant
improved PFS
in BRCA mut
(HR 0.27) /
HRd (HR 0.62)
(measured by
LOH high)

CURRENT INDICATIONS IN OVARIAN CANCER
the gain is greatest in those with a BRCA1/2 mutation >non BRCA HRd > no HRd
DR SHRUTHI SHIVDAS
(PAOLA1)
mutation status
MAINTENANCE IN RECURRENT SETING
 Maintenance therapy for recurrent ovarian
cancer in CR/PR to platinum-based CT regardless
 Maintenance therapy for recurrent
ovarian cancer in CR/PR to platinum-
based CT regardless of BRCA mutation
status
 Maintenance therapy for
recurrent ovarian cancer in CR/PR
to platinum-based CT regardless
MONOTHERAPY IN RECURRENCE
 >=3 LINES with gBRCA mutations
 PS/PR
 >=3 LINES with HRD / BRCA
 PS/PR if BRCAm; PS if HRd
 >=2 LINES WITH s/gBRCA mutations
 PS/PR
REGARDLESS of
BRCA / HR status
The NCCN Panel feels
that rucaparib is
preferred for patients
with PR-ROC, because
there are fewer good
options for this setting.

PARP I – PHARMACODYNAMICS
The PARP inhibitors differ in their ability to cause PARP trapping.
Increased PARP trapping has been shown to be associated with high
myelosuppresion.
Niraparib has highest bioavailability and PARP trapping.
Rucaparib inhibits PARP3, in addition to 1 & 2. Since PARP3 has been
reported to activate the enzymatic activity of PARP1 in the absence of
DNA, the additional inhibition of this member of the PARP family might
potentiate the effects of rucaparib compared with olaparib or niraparib.
DR SHRUTHI SHIVDAS

PARP I – HAEMATOLOGICAL
TOXICITY
DR SHRUTHI SHIVDAS
Anemia :
Niraparib – 55% any
grade ; 25 % G ¾
Olaparib – 44% any
grade ; 19% G 3/4
Rucaparib – 37% any
grade ; 19% G3/4
Neutropenia
18-30%
Niraparib – 20% G3/4
Rucaparib – 7% G3/4
Olaparib – 5% G3/4
Thrombocytopenia
Niraparib – 61% any
grade ; 34 % G ¾
Rucaparib – 28% any
grade ; 5% G3/4
Olaparib – 14% any
grade ; 1% G3/4

PARP I – COMMON A/E
Fatigue / Asthenia is a nearly universal toxicity for all PARP inhibitors and
seems to be a class effect. 59-69%
75% pts have nausea;3–4% of patients had grade 3 or 4 nausea.
 Daily prokinetic and antihistamine (eg, 5-HT3) drugs are generally helpful.
 Having a light meal with an antiemetic 60 min before taking the PARP inhibitor.
 Recalcitrant nausea or vomiting can be addressed through appropriate use of a variety
antiemetic drugs, such as metoclopramide, prochlorperazine, phenothiazine,
dexamethasone, olanzapine, haloperidol, or lorazepam.
 Aprepitant should be avoided with olaparib since it is a strong CYP3A4 inhibitor and
might affect olaparib plasma concentrations
Constipation (38%), vomiting, and diarrhoea, of any grade by 20–40%
 grade 3 or 4 toxicities occurred in 4% of patients or less with all three drugs.
Dyspepsia and Dysguesia more with rucaparib. Proton pump inhibitors and
prokinetics can be prescribed to alleviate these symptoms.
DR SHRUTHI SHIVDAS

PARPI – SPECIFIC A/E
Rucaparib inhibits MATE1 and MATE2-K renal transporter proteins, which have a role in
the secretion of creatinine. Similarly, veliparib interacts with these same proteins as well
as the OCT2 transporter….._ elevated S Creatinine
 Niraparib not associated with creat elevation
Olaparib and rucaparib – hypomagnesemia – 14%
Rucaparib led to increased cholesterol of any grade in 40–84% of patients, although only
2–4% of patients had grade 3 or 4 elevation.
Rucaparib and Niraparib has also been reported to cause an any-grade increase of
SGOT/PT in 36% of patients
Rucaparib had higher rate of SB obstruction in ARIEL2 (5%)
Discontinuation rates :10 - 15%
LESS COMMON (<15% ANY GRADE) : NEUROLOGICAL; CARDIOVASCULAR; CUTANEOUS
SECOND MALIGNANCY : <1%
DR SHRUTHI SHIVDAS

PARPI – SPECIFIC A/E
DR SHRUTHI SHIVDAS

PARP INHIBITORS: DOSING AND DOSE
MODIFICATION
Olaparib[1] Rucaparib[2] Niraparib[3]
Available forms Capsules: 50 mg
Tablets: 100 or 150 mg
Tablets:
200, 250, or 300
mg
Capsules: 100 mg
Dose Capsules*: 400 mg BID
Tablets*: 300 mg BID
600 mg BID 300 mg OD
Monitor CBC at baseline and
monthly thereafter
CBC at baseline and
monthly thereafter
 CBC weekly for the
first mo, then
monthly for the
next 11 mos, and
then periodically
 BP and heart rate
monthly during the
first yr and then
periodically
*Capsules and tablets are not interchangeable.
 Olaparib is transitioning from capsules (original FDA approval) to tablets for the maintenance and recurrence
therapy indications. Olaparib tablets (100 mg and 150 mg) should not be substituted with olaparib capsules
(50 mg) because of differences in the dosing and bioavailability of each formulation.
 Baseline wt >77 kg / PLC <1,50,000 should receive niraparib at 200 mg/ day.
2 tabs od same time every
day
3 tabs bd same time every
day

DOSING PROTOCOL - NCCN
DR SHRUTHI SHIVDAS
100 MG,90
Capsules, Rs
144999 /box
(1MONTH)
₹ 54,000 (Bottle of 60)
for 300 Mg dose &
MRP ₹ 45,000 (Bottle
of 60) for 200 Mg
dose.
50,000 FOR
56 X 150
MG TABS
(2 WEEKS)

PARP I
Management of haematological
toxicity
Consider transfusion for Hb<8 %
or sym anemia /platelet if
<10,000 or if bleeding
 Erythropoetic Fmay be used
Neutropenia G4 lasting for >5
days : hold dose ; give GCSF;
restart at reduced dose
Withhold for maximum of 28 days;
resume PARP inhibitor at reduced dose; if
already at the lowest dose, discontinue;
Niraparib ; If PLC low , reduce dose
Discontinue if haemoglobin /
WBC/ PLC has not returned to
DR SHRUTHI SHIVDAS
Poersistent nausea needing daily antiemetic
measures , reducing PS or causing wt loss >= 5%
will need dose reduction
ASCO 2020

PARP I DOSE MODIFICATIONS
100 mg tabs also available
₹ 54,000 (Bottle of 60)
for 300 Mg dose &
MRP ₹ 45,000 (Bottle
of 60) for 200 Mg
dose.
100 MG,90
Capsules, Rs
144999 /box
(1MONTH)
DR SHRUTHI SHIVDAS

HOW TO SEQUENCE THERAPIES IN
ROC?
Classes of biological therapy currently indicated to treat recurrent
ovarian cancer for patients with potentially platinum-responsive
disease, are bevacizumab and PARPi (olaparib, niraparib and
rucaparib)
In selecting next therapy for recurrent disease, four clinical scenarios
can be defined based on patients’ previous exposure to biological
therapy:
Scenario 1: chemotherapy only; no previous bevacizumab, no
previous PARPi;
Scenario 2: chemotherapy plus PARPi, no previous bevacizumab;
Scenario 3: chemotherapy plus bevacizumab, no previous PARPi;
Scenario 4: chemotherapy plus bevacizumab plus PARPi. DR SHRUTHI SHIVDAS

SCENARIO 1
TARGETTED
THERAPY- NAÏVE PT
High disease burden
DR SHRUTHI SHIVDAS
ESMO ESGO 2019
NO ROLE
FOR PARPi
NO ROLE
FOR PARPi
+ BEVAC

SEQUENCING TARGET THERAPIES
IN ROC
Scenario2: chemotherapy plus PARPi, no previous bevacizumab
In potentially platinum-responsive patients with previous exposure to
a PARPi, ESMO-ESGO guidelines recommend platinum-based
rechallenge plus bevacizumab
DR SHRUTHI SHIVDAS
Scenario3 : chemotherapy plus bevacizumab, no previous PARPi;
In potentially platinum-responsive patients previously exposed to bevacizumab, platinum-
based rechallenge followed by PARPi maintenance therapy is effective irrespective of BRCA
mutation and HRD status .
Olaparib , niraparib or rucaparib can also be considered for use as monotherapy in
patients with recurrent disease who have received several previous lines of treatment
Scenario 4: chemotherapy plus bevacizumab plus PARPi.
As this scenario is relatively recent, evidence is currently insufficient to recommend a general
approach to managing recurrent disease in patients treated with the PAOLA-1 regimen.
second-line options for patients who relapse after exposure to both agents are likely to be
limited to platinum- or nonplatinum-based regimens without additional maintenance therapy.
Bevacizumab MAY be reintroduced (NOT endorsed by ESMO)

BEVAC RETREATMENT IN PSROC AFTER FIRST
LINE BEVAC REGIME
DR SHRUTHI SHIVDAS
406
2018
For first PSROC, rechallenge with BEV in
combination with platinum-based doublets is
associated with a significantly prolonged PFS, with
no unexpected toxicity.
Longest PFS benefit was observed in paclitaxel
+ carboplatin therapy (10.1%) combined with
bevacizumab

CAN PARPI BE RE-USED? HOW DO
YOU ASSESS RESISTANCE? WHAT
TO DO NEXT?
2 very small RS studies including pts with prior PARPi, showing
responses to repeqt use.
QUADRA study of Niraparib had many pts with prior PARPi - they had
progressed.
Ongoing : OReO trial; PSROC; BRCA m & wt; prior PARPi treated;
randomized to placebo / olaparib after chemotherapy CR/PR.
CURRENTLY; no results available.
”If you have a patient who received a frontline PARPi, didn’t progress on
it, and then recurs, the best clinical predictor is still PLATINUM
SENSITIVITY. If the patient responds to platinum-based chenotherapy,
you can try PARPi as maintenance again” DR SHRUTHI SHIVDAS
NOT ENDORSED BY ASCO / ESMO

WHEN TO STOP
PSROC : In the OCEANS and GOG 213 trials, maintenance therapy with
bevacizumab treatment was stopped upon disease progression.
PRROC : In the AURELIA trial , bevacizumab was not offered alone as a
maintenance therapy; chemotherapy in combination with
bevacizumab was continued to progression.
Consideration should be given to continuing bevacizumab until
symptomatic progression or the next line of treatment is started. (if
biochemical / radiological)
Currently, the recommended length of PARP inhibitor treatment,
based on these results, remains unclear. However, treatment beyond
progression, until the next line of chemotherapy should be
considered, and may have clinical value.
DR SHRUTHI SHIVDAS

FDA
DR SHRUTHI SHIVDAS
FIRST relapse
2L
Platinum
Resistant
ROC
nonPl
+/_BEV
Later Recurrences
CR/PR
to
patinum
basedCT
Maintenan
ce with
O/R/N
Heavily
pretreate
d not on
CT
Monotherapy
with O/R/N
if BRCA m
(PS/PR)
N if HRd &PS
Pl / non Pl
CT +/_
BEV
Restricted
to 3L in Pl
resistant
FIRST LINE
1L
>2L

DR SHRUTHI SHIVDAS
Monotherapy

IMMUNOTHERAPY
PASSIVE
1. Cytokines
2. Monocolonal Ab
ACTIVE
Therapeutic Vaccines
Adaptive T cell THerapy
DR SHRUTHI SHIVDAS

IMMUNOTHERAPY
I. Monoclonal Antibodies (PASSIVE)
1. Against specific tumour antigens
2. Directed at Immune checkpoint Inhibition (Immune Checkpoint Inhibitors)
DR SHRUTHI SHIVDAS

THE IMMUNE CHECKPOINT & ITS INHIBITION
Tumor antigens are presented to T-cells by APCs via the
interaction of the MHC and the T-cell receptors,
representing the primary signal for activating T-cells.
(Cognitive phase)
Later on, there is direct interaction between Tcell and
tumor cell (effector phase)
Several negative modulators downregulate the activity
of T-cells, as a part of self- tolerance
• The CTLA-4 is induced in T-cells at the time of
their initial response to antigen; it binds to B7
with greater affinity than CD28, resulting in
specific T-cell inactivation.(cognitive phase)
• The PD-1/PD1-L1 pathway – Later
inflammatory signals from continuous Tcell
activation in the tissue induce the expression of
PD1-L1s on tumor cells.
This mechanism is also exploited by tumor cells to
evade the immune system response.
• Monoclonal antibodies that block either CTLA-4 or
PD1/PD1-L1 increase cytotoxic T-cell activity by
expanding T-cell activation and proliferation.
Interaction between B7 on
APCs and CD28 on T-cells
is needed to complete T-cell
activation and expansion.
B7 (APC) – CTLA4
binding in cognitive
phase T cell resopnse
and PDL1 (tumor cell) –
PD1 (Tcell) binding DR SHRUTHI SHIVDAS

IMMUNE CHECKPOINT INHIBITORS
Effector Phase
Direct Tr cell-Tcell interaction in tumour
Cognitive Phase
APC -Tcell interaction in lymphnode DR SHRUTHI SHIVDAS

THERAPEUTIC
VACCINES (ACTIVE)
DR SHRUTHI SHIVDAS
A T cell response against tumour
antigens can be induced by either
vaccinating with the proposed antigen in
a bid to create a natural T cell response
in vivo or by generating tumour antigen-
specific T cells ex vivo and infusing them
back to the patient.

ADOPTIVE CELL THERAPY (ACTIVE)
uses the patient’s own immune cells by
1. extracting T infiltrating lymphocytes from tumor tissue (TILs)
levels of antigen-specific T cells produced are more than 10 times that seen
with traditional vac- cine therapy
2. engineering autologous T cells with tumor antigen–specific surface receptor
molecules
 Utilises GENE THERAPY
DR SHRUTHI SHIVDAS

CAR-T (Chimeric Antigen Receptor – T
Cell ) THERAPY
DR SHRUTHI SHIVDAS

FDA - ICI
Target Drug Approv
al year
Indication Administration
Anti-
PD-1
Pembrolizum
ab (Keytruda,
Merck)
2017 EC
Unresectable or metastatic, with a
biomarker as MSI-H or dMMR
200 mg IV over
30 min every 3
weeks upto
disease
progression or /
toxicity / upto 24
mo withput
progression
2018 CC
Recurrent or metastatic, with disease
progression on or after
chemotherapy, and expressing PD-
L1
Anti-
PD-1 +
VEGFi
Pembrolizum
ab (Keytruda,
Merck) + lenv
atinib
(Lenvima,
Eisai)
2019* EC
Advanced disease without MSI-
H/dMMR who have disease
progression following prior systemic
therapy, but are not candidates for
surgery or radiation
Lenvatinib 20 mg
orally once daily
with
pembrolizumab
200 mg IV over
30 min every 3
weeks
DR SHRUTHI SHIVDAS
Additional Indications by NCCN
Pembrolizumab for TMB- H Uterine Sarcoma
Nivolumab for MSI-H endometrial carcinoma progressing on conventional treatment.
Pembrolizumab /Nivolumab for Resistant GTN
PDL1expression
measured in terms of
CPS(Combined
Positive Score) >1

A/E -PEMBROLIZUMAB
MC S/E (>30%) are Anemia, Fatigue, hyperglycemia,
hyponatremia, hypoalbumineia, cough, nausea.
Approximately 10% of patients receiving anti-PD-1 antibodies
have grade ≥3 AEs.
The most common immune related AEs among patients in the
nivolumab& pembrolizumab are endocrinopathies (mostly
thyroiditis), pneumonitis, hepatitis, diarrhoea and colitis.
Fatigue, pruritus and nausea (of any grade) were also reported in
>15% of patients.
most AEs occur within the first 6 months of treatment.
DR SHRUTHI SHIVDAS
INR 1.5 L
/ 100 mg

CA ENDOMETRIUM- TCGA
Subgroup of endometrial Ca’s beneftting from ICI:
 As MMRd- and POLE-deficient tumours exhibit a high tumour mutation burden
(TMB), there is increased expression of highly immunogenic tumour neoantigens
which stimulate lymphocytic infiltration as well as up-regulation of inflammatory
cytokines.
subgroup of endometrial cancers may benefit from PARP inhibitor
therapy.
 PTEN, which regulates the expression of RAD51 and reduces the incidence of
spontaneous dsDNA breaks, is altered in more than 80% of endometrial cancers.
 approximately 15% of copy-number high (serous-like) endometrial cancers
display a predominant HRR-deficient genomic signature.
A number of clinical trials are currently ongoing evaluating the role
of PARP inhibitors in endometrial cancer
DR SHRUTHI SHIVDAS

EOC – TCGA (2011)
There are four subtypes of HGOC in the gene expression profile
(differentiated, immunoreactive, mesenchymal, and proliferative), and
patients with the mesenchymal subtype showed the worst prognosis.
Recent bioinformatics and clinicopathology approaches have shown that
 the mesenchymal subtype is more sensitive to paclitaxel and fits the dose-dense
paclitaxel and carboplatin chemotherapy.
 Bevacizumab may improve the survival of patients with mesenchymal and proliferative
subtypes, but not those with the immunoreactive subtype.
Immunoreactive more likely to respond to ICI.
Ovarian cancer is classified as a ‘cold tumour’ with low TMB and lack of T cell
infiltration which may, in part, explain the low response rates to ICI
monotherapy.
Thus, selection of drugs will be done according to molecular analyses
DR SHRUTHI SHIVDAS

PERSONALIZED MEDICINE Tumor Agnostic Therapy
Master Trials
DR SHRUTHI SHIVDAS

EVOLVING FRAMEWORK OF CLINICAL
TRIALS IN ONCOLOGY
Trials have shifted from
enrolling (i) unselected
patients exclusively based
on the type of tumor /
tissue of origin
an exquisite, appropriate
selection of biomarker-
defined populations either
(ii) within a specific tumor
type
(iii) across a variety of
different cancers that share
a common molecular
abnormality. DR SHRUTHI SHIVDAS

TUMOR / TISSUE- AGNOSTIC
THERAPY
A tumor-agnostic treatment is drug treatment that is used to treat
any kind of cancer, regardless of the organ or the type of tissue from
which it developed.
Tumor-agnostic therapy uses the same drug to treat all cancer types ,
purely based on the presence of a genetic mutation or biomarker that
is targeted by the drug.
It is a subtype of targeted therapy
Evaluated in MASTER TRIALS.
DR SHRUTHI SHIVDAS

MASTER PROTOCOLS
“
A master protocol refers to a single,
overarching design developed to evaluate
multiple hypotheses with the general goal of
improving efficiency and a more ethical
approach to trial evaluation.
1. basket trial, in which a single targeted
therapy is evaluated for multiple diseases
that share common molecular alterations
or risk factors.
2. umbrella trial, in which multiple targeted
therapies are evaluated for a single disease
that is stratified into multiple subgroups
based on different molecular or other
predictive risk factors
3. platform trials” as any clinical trials that
allowed for the intervention arm(s) to be
DR SHRUTHI SHIVDAS

Patients enrolled in a basket trial will represent multiple diseases with a common, unifying
predictive risk factor; and, in umbrella trials, patients with a common disease (a single disease)
will be recruited and enrolled. DR SHRUTHI SHIVDAS

no umbrella trials have led to FDA approvals currently (February 2020).
DR SHRUTHI SHIVDAS
NRK fusion gene +
Rec / metastatic
Ca Endo and uterine
sarcoma

CONCEPTUAL APPROACHES FOR
TARGETTED THERAPIES IN
CANCER
while the PARP
locus is
occasionally
deleted in
human cancers,
it is very rarely
deleted in BRCA
mutant tumors.
DR SHRUTHI SHIVDAS

TAKE HOME
Oncogene payhways, SSB repair , IC and cancer antigens can be targeted
IMMUNE and GENE therapies are sub categories
Bevac, PARPi, Pembrolizumab – recent FDA approvals
EOC : 1st line :
 Olaparib only in BRCA
 Bevac + Olain HRd
 Niraparib irrespective of BRCA / HRd
ROC
 Pl Res – CT vs CT + Bev ; No role of PARP I
 PlSens- CT + Bev OR CT + O/N/R if CR/PR
 >2L: O/R/N Monotherapy ; BEV + CT if PS; Bev + CT if PR only upto 3L
Pembrolizumab : Rec/Met EC, CC if PD1+ /MMRd
 ? Role in GTN
DR SHRUTHI SHIVDAS
BRCAm - Ola / Nir/ Bev + Ola
HRd – Nira / Bev + O
HRp – Nira vs Bev (adv when poor response to platinum)

Trabectedin plus PLD is currently the only nonplatinum
combination approved to treat recurrence in patients with
platinum-sensitive disease [3]. In a randomized Phase III
study in platinum-sensitive patients who had relapsed
after one line of platinum-based chemotherapy, the
efficacy of trabectedin plus PLD was superior to that of
PLD monotherapy with no impairment to quality of life
[26,27]. In a prospective observational ‘real-life’ study of
heavily pretreated patients (n = 158 evaluable) with
platinum-sensitive ovarian cancer who were treated with
trabectedin plus PLD, the overall response rate was 38%,
the disease control rate was 66.5% and median PFS was
11.4 months. The combination was effective whether
administered in the second (∼25% of patients), third
(∼34%) or fourth and later (∼40%) line of treatment [28].
The benefits observed with trabectedin in combination
with PLD between platinum lines may derive from its
multitasking mechanism of action and complementarity
with platinum. Trabectedin impairs DNA repair, inhibits
transcription, induces changes in the tumor
microenvironment [29], and may restore platinum
sensitivity by selecting platinum-responsive cancer cells
DR SHRUTHI SHIVDAS

According to most major society recommendations and guidelines,
which of the following patients with a diagnosis of ovarian cancer
should be tested for the presence of BRCA mutation?
oPatients younger than 50 years of age
oPatients with high-grade serous histology
oPatients with a family history of breast or ovarian cancer
oAll patients with epithelial ovarian cancer
To which of the following does the term "BRCAness" refer?
oA strong family history of both breast and ovarian cancers
oRapid relapse after platinum-based treatment
oHomologous recombination deficiency identified with next-generation
sequencing
oRobust sensitivity to platinum agents
DR SHRUTHI SHIVDAS

A 60-year-old patient with ovarian cancer and with no family history of ovarian cancer has just undergone
initial debulking surgery.
Based on the previous discussion, which of the following tests do you now recommend for this patient?
A. Germline test only
B. Somatic test only
C. Both germline and somatic tests
D. I do not test for BRCA status in this setting
E. Uncertain
Based on the previous discussion, which of the following therapies would you now recommend for this
patient, if gBRCA ?
A. Bevacizumab maintenance therapy
B. PARP inhibitor maintenance therapy
C. Pegylated liposomal doxorubicin plus carboplatin for 2 more cycles
D. Surgery, then one of the above choices
E. Observation
F. Uncertain
DR SHRUTHI SHIVDAS

Which of the following PARP inhibitors is approved for frontline maintenance therapy
regardless of BRCA1/2 mutation status in patients with advanced ovarian cancer with a
response to platinum-based chemotherapy?
A. Niraparib
B. Olaparib
C. Rucaparib
D. Niraparib and olaparib
E. Niraparib, olaparib, and rucaparib
F. Uncertain
v
DR SHRUTHI SHIVDAS

DR SHRUTHI SHIVDAS
NIRAPARIB maintenance vs Bevac vs nil
Bevac – perofration risk
Niraparib – IDEAL (PS is a good biomarker for
PARPi)

Targetted therapies gyn oncology

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