A Pharmacist’s Take on Navigating the Expanding Therapeutic Landscape for Endometrial and Cervical Cancers: Insights on Coordinating and Delivering Effective Modern Care

Co-Chairs Sarah Hayward, PharmD, BCOP, and Ambar Khan, PharmD, BCOP, discuss endometrial and cervical cancers in this CME/CPE/IPCE activity titled “A Pharmacist’s Take on Navigating the Expanding Therapeutic Landscape for Endometrial and Cervical Cancers: Insights on Coordinating and Delivering Effective Modern Care.” For the full presentation, downloadable Practice Aids, and complete CME/CPE/IPCE information, and to apply for credit, please visit us at https://bit.ly/3wGBPQp. CME/CPE/IPCE credit will be available until May 27, 2025.

1. A Pharmacist’s Take on Navigating
the Expanding Therapeutic Landscape

for Endometrial and Cervical Cancers
Insights on Coordinating and Delivering Effective Modern Care

Sarah Hayward, PharmD, BCOP Ambar Khan, PharmD, BCOP
Clinical Pharmacy Specialist Oncology Clinical Pharmacist -
Gynecologic Oncology Outpatient Gynecology/Oncology
Stephenson Cancer Center The James at OSU

at OU Health Wexner Medical Center

Oklahoma City, Oklahoma Department of Pharmacy
Columbus, Ohio

Go online to access full CME/CPE/IPCE information, including faculty disclosures.

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2. Our Goals for Today

Improve your knowledge on the mechanism of action of immune
checkpoint inhibitors and discuss the latest evidence supporting the
use of immunotherapy in endometrial and cervical cancers

Provide insight on the importance of molecular testing in endometrial
and cervical cancers and how this can affect treatment planning

Offer guidance for pharmacists to develop collaborative practice
strategies with the care team to address practical aspects of care,
including staff education, patient counseling, adverse event
management, and safety and dosing considerations

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3. How Common Is Endometrial Cancer?!

Cases by Stage

Q Across all cancer types in the Unknown,
United States, uterine cancer represents e
3.4% of new cases 2.2% of deaths Aci
“fom
Estimates for 2022 Localized,
67,880 new cases 13,250 deaths ad

5-Year Relative Survival by Stage
100, %48

63 years & ie

age at diagnosis

80.8% 20
5-year relative survival (2014 o
Localized Regional — Distant Unknown

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5-Year Relative
Survival, %

1. ps sr cancer govstaacistcor him

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4. How Common Is Cervical Cancer?!

5 Cases by Stage
Q Across all cancer types in the Unknown,
United States, cervical cancer represents a
0.7% of new cases 0.7% of deaths Loc
| Estimates for 2024 |
Regional
13,820 new cases 4,360 deaths aad

5-Year Relative Survival by Stage

91
50 years

median age at diagr 60.8 614

67.4%
5-year relative survival (2014-2

1. ps soer cancer govistatfactsimlcerix hr. PeerView.com

Localized Regional — Distant Unknown

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5. Survival Disparities: Endometrial vs Cervical Cancers’?

+ Overall, mortality rates for endometrial \

cancer are increasing (2% annually,
2008-2018)
+ However, the burden for Black patients
has increased disproportionately and
now represents one of the largest o
racial disparities in cancer settings
Significant racial disparities are also
seen with cervical cancer mortality
rates
Furthermore, Black and Hispanic
women are more likely to be
diagnosed at a later stage

3

Uterine Cancer
Mortality Rate (per 100,000)
oney eu Ae

1000. ” 2015: 100. 2008
1 201 1004 201

LS

AelanPaeine

Cervical Cancer
Mortality Rate (Per 100,000)

Hispaie Any” Nonhispanic ” Nenhispanie ” Nontispanie ” Nontispaic
Race) Amerkan AsionPadtle "Black wns

ae a
1.Monk BJ et al. Gynecol Oncol 2022:164:325-332.2. tip:Isoe.cancer govsalfctihtmlcerichtmi. 3. Holt HK ot al. JAMA Netw Open. 2025:6:6232085. PeerView.com

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6. Shifting the Paradigm:
Personalizing Treatment With Molecular Profiling!

POLE (ultramutated) Ge or
: ‘endometrial cancers

POLE: ultramutated, High mutation burden leads to better

Copy-number low 100-500 mutations/Mb immune response; excessive mutations,
(endometrioid) lead to inability to proliferate
MSI (hypermutated) dMMRIMSI-H: + 20%-30% of endometrial cancers
10-20 mutations/Mb + Hereditary (Lynch syndrome) or somatic

Copy-number high

Progression-Free Survival, %

(serous like) + Most common endometrial cancer
CNIoWNSMPITPSS || gate
ME + Estrogen/progesterone positive

der + PTEN, PIK3CA, ARIDIA, and KRAS
¡pic mutations.
Log-rank P = .02
CN high/TP53 abn:
2 40 60 60 10 120 Ha + Often serous or mixed histology
. aoe + Poorest prognosis
Time, mo
1. The Cancer Genome Atos Research Network. Nature, 2013:487:67-73, PeerView.com

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7. MMR and MSI"?

MMR Protein (IHC Test) MSI (Molecular Test)

* MMR protein complexes (MLH1 + PMS2 and + Consensus definition: MSI is a condition of
MSH2 + MSH6) detect and correct mistakes genetic hypermutability
during DNA replication + MSlis characterized by mutation clustering

+ Absence/loss of function in one of the four MMR: in microsatellites typically consisting of repeat
proteins results in dMMR length alterations

Phenotypic evidence that MMR is not

The presence of MSI represents
MMR is the cause of MSI-H
functioning normally (dMMR)

MSI-H provides phenotypic evidence of dMMR;
thus, MSI-H and dMMR are considered biologically the same population

+ dMMR/MSI-H refers to patients with mismatch repair deficiency
+ pMMRIMSS refers to patients with mismatch repair proficiency

4. Kloor M ot al. Trends Cancer 2016:121-133,2. Luchi C et a. Ann Oncol. 2019;20:1282-1243, 3. NCCN Cínical Practice Guidelines in Oncology. Uterine er:
"Neoplasms. Version 2 2024 hits:www.ncen.orpiprofessionalsiphysican_ols/pduteine pat PeerView.com

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8. Immune Checkpoint Inhibitors Block
T-Cell Inhibitory Signals

PD-1/PD-L1 Checkpoint Inhibition
* Immune checkpoint inhibitors work by blocking
T-cell inhibitory signals (ie, removing the brake

Without vn
2 inmunoterapy | inmune on the immune system)

5 + The cancer immunotherapy landscape is rapidly
5 expanding; benefits of immune checkpoint

ha] blockers are seen across different tumor types
£ and treatment settings (as single agents and

Ca combinations)

3 ‘oT Cel

8 + Predictive biomarkers can guide clinical

La Tumor escape Elmnaton of decisions regarding the use of immunotherapies

Tumor cell

Improved responses occur with checkpoint ii tors in dMMR/MSI-H tumors,
whereas chemotherapy and targeted agents may have lower responses

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9. The Pharmacist and the Wider Care Team
in Endometrial and Cervical Cancers

Onboarding and operational
role of newer therapeutics
Ensuring medication access
Educating staff and care team
Educating patients and
caregivers
Practicing medication therapy
management
Patient with Assessing patients and
endometrial/ managing AEs
cervical cancer

Educating patients, managing AEs,
and navigating care

Oncologist athologist

Assessing patients and

planning treatment Molecular testing

ase
progression

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10. How Immunotherapy Is Changing
the Practice of Endometrial Cancer Care
The Pharmacist's Role

Ambar Khan, PharmD, BCOP

Oncology Clinical Pharmacist - Outpatient Gynecology/Oncology
The James at OSU Wexner Medical Center Department of Pharmacy
Columbus, Ohio

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11. Introduction to Catherine’s Case: A 65-Year-Old

Patient With Metasta

Patient Case

A 65-year-old woman presented
with a 3-month history of abnormal uterine
bleeding; physical examination revealed
an enlarged uterus and tenderness
upon palpation

Clinical workup revealed grade 3

endometrioid adenocarcinoma (stage IVB,

ECOG PS 0) with a large uterine mass and
pulmonary metastasis

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Endometrial Cancer

For Discussion

In developing a treatment plan for this
patient, what important factors should the
pharmacist be considering?

What patient-specific factors would you take

into account (eg, genetics, medical history,
current medications)?

What is the role of the pharmacist in patient
education on safety management?

How can the evidence guide us in patient
consultation and clinical decision-making?

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12. Clinical Consult: The Role of the Pharmacist
in Developing a Treatment Plan for This Patient

© Coordinate any needed referrals

©

Li Assess need for dose adjustments

© Prepare to counsel the patient and staff on safety expectations

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13. Molecular Profiling for 1L Metastatic/Recurrent EC:
Where Does Immunotherapy Come In?

POLE/MMRd/MSI-H i MMRp/MSS

Pac/carbo/
ICI > ICI
maintenance

Pac/carbo/ICI > ICI
maintenance (RUBY/
NRG-GY018) pending)

Pac/carbo/
trastuzumab/|
pertuzumab
(NRG-
GY026
pending)

Side courtesy of Kathleen N. Moore, MO, MS. PeerView.com

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14. Combination Approaches: Leveraging ICI Activity’

Immunotherapy Alone Immunotherapy + Chemotherapy
%

eve ret Mme mer

microenvironment

e.

Pies

1. Baily C ot a. NAR Cancer. 2020:22c08002.

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The combination of

immunotherapy and

chemotherapy can

increase tumor sensitivity

to PD-L1-targeted mAbs

Chemotherapy

— Induces upregulation of
PD-L1 on cancer cells

— Facilitates infiltration of
CD8+ T cells and NK cells

— Increases maturation of
APCs (including dendritic
cells and tumor
macrophages)

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15. Frontline Approaches in Endometrial Cancer:
Immunotherapy + Chemotherapy

Phase 3 RUBY (Part 1): Dostarlimab + Chemotherapy??

Key Eligibility Criteria
Advanced or recurrent
endometrial cancer
not treated with
chemotherapy
Previous adjuvant
chemotherapy allowed
if completed 26 mo ago
ECOG PS 0-1

+ Microsatellite

Stratification

Dostarlimab 500 mg +
carboplatin/paclitaxel
Q3W for up to 6 cycles

status (MSI-H
vs MSS)
Disease status
(stage III vs IV
vs recurrent)
Prior pelvic
radiotherapy
(yes vs no)

Placebo +
carboplatin/paclitaxel

Primary endpoints: PFS and OS
Secondary endpoints: ORR, DOR, safety, and PRO

1. ips Ina govistudy/NCTOI81796. 2. Mirza MR et al. N Engl Med. 2023:388:2145-2158

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Dostarlimab
1,000 mg
W for up to 3 y

Placebo

for up to 3 y

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16. Phase 3 RUBY (Part 1): Improved Survival
With Dostarlimab + Chemotherapy’?

Substantial PFS Benefit in dMMR/MSI-H Population ‘Substantial OS Benefit in dMMR/MSI-H Population®
Median duration of HR2032
x followup, 66m — (GEN 01.017063)

u : Pe code

> H Dostarimab + CP
xe 3
Ez (5% 1.462734) 2

= i Damme cP NENENE) | 1253028)

> Placebo CP SIAGOSNE) À 3565 638)

a | | iszemarrzen Os matty amigos) | sense mmunatmerpy

Time Since Randomization, mo Timo Since Randomization, mo

July 2023: FDA approved for dMMR pati pulation:

"08 in the dMMRIMSI-H and MMRpIMSS populations was a prespecified exploratory endpoint. » Median expected duration of follow-up; range 31.0-48.7 months.
4 Mica MR et al. N Engl J Med. 2029:308 2145-2158. 2. Powell MA et al. SGO 2024, Abstract LBAT. 3. ps. a. govidrugelsng-approval-and-databacentsa-
_approves-dostarimab-gny-chemotherapy-endomatnak.cancor. PeerView.com

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17. Frontline Approaches in Endometrial Cancer:
Immunotherapy + Chemotherapy

Phase 3 NRG-GY018: Pembrolizumab + Chemotherapy’?

PR or SD
Key Eligibility Criteria
Pe li Pe li

- Rance orrcument | | Statiteaton | | Lee

EC + dMMR status Q3W for up to up to 14 cy
+ No previous (yes vs no)

chemotherapy + ECOG PS

for EC (previous (Oor1vs2)

adjuvant chemotherapy + Prior

allowed if completed SEO

212 mo 0) AS aa
+ ECOG PS 02 -

+ Primary endpoints: PFS in pMMR and dMMR

+ Select secondary and exploratory endpoints*: OS in pMMR and dMMR, PD-L1 status (positive vs negative) in PMMR
and dMMR, INV PFS by PD-L1 status in pMMR and dMMR, and BICR vs investigator-assessed outcomes by MMR status

| MMR status as randomized Peer}.
1. ps incl goustudy/NCTO3014612. 2. Eskander RN etal. N Engl J Mod, 2023:388:2159-2170. PeerView.com

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18. Phase 3 NRG-GY018: PFS Benefit
With Pembrolizumab + Chemotherapy’

dMMR Cohort PMMR Cohort
am MPFS: NR vs 7.7 mo mPFS: 13.1 vs 8.7 mo
fe HR = 0.3 (95% Cl, 0.19-0.48) HR = 0.54 (95% Cl, 0.41-0.71)
P<.001 P<.001

Pembrolizumab + chemo

2 06
¿os Pembrolizumab + chemo
A
£ os
021 Placebo + chemo 02
01 0.14 Placebo + chemo
o o
o 6 2 8 E 3% 0 6 2 % 2% 3 36
Time, mo Time, mo
Under FDA Priority Review?
1. Eskander RN etal. N Engl J Med. 2023:388:2159-2170. 2. htps./inance yahoo commews/lda-grants-prriy-review-mercks-114600907.himl PeerView.com

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19. Phase 3 NRG-GY018: OS Benefit
With Pembrolizumab + Chemotherapy’

Favorable Trend in OS With Pembro + CT for dMMR EC Favorable Trend in OS With Pembro + CT for PMMR EC
OS data immature at IA (18% information fraction) 05 data immature at A (27.2% information fraction)
ve, Ft Diston
pre sree monos
CEE oi
ano

Fo rected porra Da)
Placebos CT PS A 19.1%) 0
Pembro + CT
: non 15970 bunten Med OS nico

I

m meme

Timo Since Randomization, mo

+ Despite high rates of post-study immunotherapy, OS analysis suggested a directionally favorable benefit
with the addition of pembrolizumab to chemotherapy in both the dMMR and pMMR EC cohorts

+ The majority of patients with EC had PD-L1 CPS 21 regardless of MMR status

+ Pembrolizumab improved INV PFS regardless of PD-L1 status for both the dMMR and pMMR populations

+ PFS by investigator and BICR were consistent
1. Eskander RN eta SGO 2024. Oral presentation PeerView.com

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20. Other Ongoing Trials Combining Immunotherapy
and Chemotherapy in the Frontline Setting’?

Phase 3 AtTEnd: Phase 3 DUO-E:
Atezolizumab + Durvalumab-Based
Chemotherapy Treatment + Chemotherapy

Atezolizumab until progression +
carboplatin/paclitaxel vs placebo + Maintenance durvalumab +

carboplatin/paclitaxel olaparib vs durvalumab +
olaparib placebo vs control

PFS was improved in the dMMR
and ITT populations
Addition of durvalumab
Coprimary endpoint of OS had a significantly improved PFS in the
trend for improvement, but data dMMR and pMMR populations
are not yet ma

1. Colombo Net al. ESMO 2029. Abstract LAD. 2, Westin SN et al. J Gin Oncol 2024:42:289-299, PeerView.com

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21. Frontline Immunotherapy vs Chemotherapy

KEYNOTE-C93'

Pembrolizumab

Primary endpoints:
PFS and OS

ORR, DCR, and DOR

Key secondary endpoints:

DOMENICA?3

Dostarlimab

Primary endpoint:
PFS

Key secondary endpoints:
OS, PROs, ORR, and DOR

LEAP-0014

Lenvatinib +
pembrolizumab

Primary endpoint
PFS and OS

Key secondary endpoints:
ORR, HRQOL, and safety

dMMR patient population

> ze

1. htpselincatials govstudyiNCTO5173967. 2. tpsIciicalils govstudyINCTOS201547. 3. Joly Feta, ASCO 2023, Abstract TPSS630,
4! bips ineaials govistudyINCTO3BE4101. 5. Mart C eta. ESGO 2024. Abstract 86, 6. Marth © et al SGO 2024, Abstract 22.

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dMMR patient population

dMMR and pMMR
patient populations

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22. irAE Grading and Management: Overall!-3

Grade 1
Minimal or no symptoms; diagnos!

Grade 3/4
Severe or life-threatening symptoms

In general, checkpoint inhibitor therapy should
be continued with close monitoring, with the
exception of some neurologic, hematologic,
and cardiac toxicities

Hold checkpoint inhibitor therapy

+ Initiate high-dose corticosteroids

+ If symptoms do not improve with 48-72 h of high-dose
corticosteroids, infliximab may be offered for some toxicities

+ Taper corticosteroids over the course of at least 4-6 wk

+ When symptoms and/or laboratory values revert to grade <1,

rechallenging with immunotherapy may be offered; however,

caution is advised, especially in those patients with early-onset

itAEs; dose adjustments are not recommended

Grade 2

Mild to mo

‘+ Hold checkpoint inhibitor therapy for most
grade 2 toxicities

+ Consider resuming immunotherapy when symptoms
and/or laboratory values revert to grade $1

+ Corticosteroids (initial dosage of 0.5-1 mg/kg/d of

prednisone or equivalent) may be administered; treat

Until symptoms improve to grade $1 and then taper

over 4-6 Wk

Grade 4
+ In general, permanent discontinuation of checkpoint inhibitor
therapy is warranted, with the exception of endocrinopathies
that have been controlled by hormone replacement

1. Postow MA et al. Eng! J Med, 2018:378:158-168. 2. Schneider BJ eta. Clin Oncol. 2021:39:4073-4125. 3. NCCN Ciical Practice Guidelines in Oncology. fs
Management of Immunotherapy-Related Toxics. Version 1.2024. hips Jww.ncen.org/protessionals/physician_gls/pdlimmunotherapy pd. PeerView.com

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23. irAE Grading and Management: Organ-Specific Toxicities!

Gastrointestinal Endocrine/Thyroid

‘Educate patents about supporive cae o maintain hydration and dietary changes;
‘Gt consultation: consider colonoscopy and EGO

Levothyroxine: adjust eves to maintain reo Ta
‘at micrange: ypicaly 1.6 mephgid

Grade 4 (<4 stools above baseline) Grade 2 (46 stools above Grade 3 66 stots above seine) || asymptomatic Cina hypotyoisen
Cons hosing Beine) Die an CR AC [cin sr iar eee ra
patea te cordon po || DN a rom y 4 menta

+ Antara: loperamide, > Predisoneny perl ms + [eones npcenent
<ipnenonateavepne Inanypeancon2 M990) Gage eat) + FS4210. 1 com > Consider ende.

+ norsponseionlsrnein > Permanent; scams een =
30, contar IV rosado Cone patentee Feeds + Ete concomitant
mb or vecizumas > Prnsone 24 mois + Tolo Town: ‘rena non
+ Forimabvedolzumab (no mponso n 234. consider onal’
tracy colt, condor nia ana) Fed
ac or uso

& Refer to NCCN

Educate patients about supporive care and sun protection (eg. sunscreen, sunglasses) Guidelines
Moderato grade 2 (10%-30% BSA) ‘Severe grade 34 (30% BSA)

‘Continue ct Hasıcı
© Treat wih moderate-potency Treat wih Nop-poteney opel steroids

steroids + Prednisone 0.5.1.0 magi (neroase up
+ Gratanthistamines 102.0 maha, not responsive)
+ Topical emotions + Adit for management

and dematoiogy consu

1. Postow MA tal. N Engl J Med, 2018:3/8:158-168, 2. Schneider BJ ol a. J Clin Oncol 2021:39-4073-4125. 3. NCCN CiricalPracice Guidelines in Oncology. a
Management of Immunotherapy-Related Toncies. Version 1.2024. hips Jiwww.ncon.orpiprotessionalsiphysician_glsipdlimmunotherapy pd. PeerView.com

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24. Immune-Related Adverse Events Can Occur at Any Time

Variable Timing of irAEs*

Patient Communication
Is Essential

Colitis Pneumonitis (ar)

+ Discuss potential onset,
duration, and symptoms
of IRAEs
+ Patients may be more
Nephritis likely to adhere to treatment
when they have a full
picture ofirAEs

Skin
rash or
pruritus

Toxicity, Grade

Endocrinopathy

Duration of Treatment, wk

1.Marins F ot al. Not Rev Clin Oncol. 2019;16:563-580, PeerView.com

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25. Back to Catherine’s Case: Practical Considerations
for Combining Immunotherapy With Chemotherapy

A 65-year-old woman presented with a 3-month
history of abnormal uterine bleeding;
physical examination revealed an enlarged
uterus and tenderness upon palpation

Clinical workup revealed grade 3 endometrioid
adenocarcinoma (stage IVB, ECOG PS 0) with
a large uterine mass and pulmonary metastasis

IHC reveals pMMR status, HER2 negative

The care team elects to initiate a frontline
pembrolizumab + chemotherapy regimen

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For Discussion

Why was this regimen selected? What is the
mechanism of combining chemo + 10?

How do you manage dosing/scheduling for
this regimen, and how would you plan to
educate the patient on this information?

What strategies would you consider for
patient education on irAEs?

How would you advise the patient if she
experiences colitis after 1 month of
treatment?

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26. Personalized Treatment Plans in the Second-Line Setting

Until recently, the backbone of
1L treatment was mostly carboplatin and paclitaxel

1s follow

2L therapy

In this scenario, immunotherapy emerged as a
game-changer in the management of endometrial carcinoma

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27. Combination Approach: Lenvatinib + Pembrolizumab*3

FDA Approval Indication

Pembrolizumab in combination with lenvatinib for the treatment of
patients with advanced endometrial carcinoma that is pMMR or
not MSI-H, who have disease progression following prior
systemic therapy in any setting and are not candidates for
curative surgery or radiation

2019 accelerated approval,
2021 full approval

The initial approval was based on data from the
phase 2 KEYNOTE-146 single-arm trial that enrolled 108 patients

with metastatic endometrial carcinoma that had progressed
following at least one prior systemic therapy in any setting and
showed promising antitumor activity with the combination regimen

Joa (amare) Pesca lomera, nip acess ta gorge, ocsaba/2024/1256 1491604 at na
2 Maler V etal Lance Oncol 201920711718. 3. Maker Via Y Cin Oncol 20208 29 PeerView.com

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28. Phase 3 KEYNOTE-775: Lenvatinib + Pembrolizumab*

Stratification
Key Eligibility Criteria MMR status (pMMR vs Lenvatinib
+ Advanced, metastatic, or dMMR) and further D+ PFS, OS, and
Tecurrentendomeinäll stratification within. pembrolizumab? ORR were
His PMMR by 200 mg statistically
+ Measurable disease by = Region ({1] Europe, significantly
BICR United States, 11 Treat until progression improved with
A À Canada, Australia, #1. or unacceptable toxicity lenvatinib +
o nore New Zealand, and pembrolizumab
Israel vs [2] rest of Doxorubi vs chemotherapy
+ ECOGPSO- the world) mg/r at the primary
+ Tissue available for + ECOG PS (0 vs 1) paclitaxel 80 analysis
MMR testing) + Prior history of pelvic wk on/1 w

radiation (yes vs no)

+ Primary endpoints: PFS by BICR and OS
+ Secondary endpoints: ORR, HRQOL, pharmacokinetics, and safety
+ Key exploratory endpoint: DOR

Patents may have received up to wo por platnum-based CT regimens if one was given in the neoadjuvant or adjuvant treatment
‘setting. Maximum of 35 doses Maximum cumulative dose o 500 mg. a e
1. Maker V et al. N Engl Y Mod, 2022:386:437-448, PeerView.com

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29. KEYNOTE-775: Continued Benefit

With Additional Follow-Up in the pMMR Populationt22

Median PFS (95% CI) Median OS (95% Ch
Won, Lenvatini + pembrolzumab: 6.7 mo (5.6-7.4) 100 LLenvatinib + pembrolizumab: 18.0 mo (14.9-20.5)
20] Chemotherapy: 3.8 mo 0.650) Xo Chemotherapy: 12.2 mo (11.0-14.1)
_ so] Ly HR forprogression or death = 0.60 (95% Cl, 0.50-0.72) fo HR for death = 0.70 (95% C1,0,58.0.3)
HE Än
Es © ¿o
23% En Lenvatinib +
E ee ee
a2 o Lina Za
a pembrolizumab qua
3
» Bo
2 a Chemotherapy

° °

765 2686 À À 7 0 à % % &
Time, mo

REREEEEFEEETEET.
Time, mo

ORR: 32.49 15.1%
CR: 5.8% vs 2.6%
PR: 26.6% vs 12.5%
mDOR: 9.3 mo vs 5.7 mo

‘Median flow in: 147 months; data cut date: March 1, 2022; >16 mont of dona folow-up fom nl pain; PFS by BICR per RECIST VI. a
1. Maker V etal N Engl J Mod. 2022;386:437-448. 2. Makkor V etal. J Cin Oncol. 2023:41:2004-2910. PeerView.com

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30. Management of AEs in IO + TKI Therapy’

* Two mechanisms of action result in 10 + TKI Combination Toxicities
two sets of AE profiles that are not
mutually exclusive

+ Itis important to determine which

therapy is causing the AE in order to
Py 9 Overlapping TKI
Hypertension

Taste changes

Hepatitis Stomatitis

— In certain cases, use appropriate crisis WI ypothyroid Dyspepsia
supportive care N AMS — Cytopenia
— If symptoms resolve in a few days, D — = HFSR

TKI was likely the cause | PRES

Consult irAE management guid:
(eg, ASCO, NCCI GO, ESMO)

4. Postow MA ta N Engl J Mod. 2018:378:158-168. 2. Schneider Bot al. J Clin Oncol, 2021;39:4073-4126. 3. NCCN Cinical Practice Guidelines in Oncology.
Management of immunotherapy Related Toxictes. Version 1.2024. ps www.necn.orgprofessonals/physician_glspdlimmunotherapy pat re
4. 0 Coarbhail RE et al. Gynecol Oncol 2022:166:25-35. PeerView.com

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31. Case Variation: What If the Patient Had
Initiated Second-Line Immunotherapy + TKI?

Patient Case

A 65-year-old woman presented with a 3-month
history of abnormal uterine bleeding;
physical examination revealed an enlarged
uterus and tenderness upon palpation

For Discussion

Clinical workup revealed grade 2 + What are the treatment options in this setting?
endometrioid adenocarcinoma (stage IIIC1) + Assuming the patient is placed on a 2L
pembrolizumab + lenvatinib regimen, how would you
IHC reveals pMMR, HER2 negative plan'to address: dosing?

+ How would you manage toxicities? Are there

á fe t ?
See maileiäryclnd? overlapping toxicities to consider

carboplatin/paclitaxel and subsequently + What are the logistical considerations with timing for
repens
progresses after 4 months IV and oral combinations? Are there prior
authorization/approval barriers with insurance?

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32. The Pharmacist's Perspective
on the Impact of Immunotherapy
for Cervical Cancer Care

Sarah Hayward, PharmD, BCOP

Clinical Pharmacy Specialist Gynecologic Oncology
Stephenson Cancer Center at OU Health
Oklahoma City, Oklahoma

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33. Introduction to Diana’s Case: A 68-Year-Old Patient
With High-Risk, Locally Advanced Cervical Cancer

Patient Case For Discussion
A 68-year-old woman presented with + What are your first steps in evaluating
postmenopausal bleeding; this patient for treatment selection?

her last pap was >10 years ago + How should the care team approach

Physical examination revealed molecular profiling to guide therapeutic
a large cervical mass, decisions?
and subsequent imaging showed
tumor invasion of the bladder

Clinical workup confirmed invasive
squamous cell carcinoma (stage IVA)

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34. NCCN Guidelines on Integrating Frontline Immunotherapy
for Recurrent/Metastatic Cervical Cancer!

First-Line Therapy
Preferred Regimens
PD-L1-positive tumors
- Pembrolizumab + cisplatin/paclitaxel + bevacizumab (category 1) Pembrolizumab may be added
- Pembrolizumab + carboplatin/pacitaxel + bevacizumab (category 1) ) Ao)
Cisplatin/paclitaxel/bevacizumab (category 1) 2014 stage Ill-IVA cervical cancer
+ Carboplatin/paclitaxel/bevacizumab
Other Recommended Regimens
Cisplatin/paclitaxel (category 1)

Carboplatin/paciitaxel (category 1 for patients who have received prior
cisplatin therapy)

Topotecan/paciitaxel/bevacizumab (category 1)
+ Topotecan/paciitaxel
+ Cisplatin/topotecan

Checkpoint inhibitors and/or
mAbs included in this regimen

may be continued as
maintenance therapy

Cisplatin
Carboplatin

1.NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer. Version 2.2024. ht: ncen org/pofessionalslphyscian_s/pdlcervical pat PeerView.com

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35. PD-1/PD-L1 Axis Controls Immune Tolerance
Within the Tumor Microenvironment!2

+ For metastatic or recurrent cervical
cancer, PD-L1 testing is required to
initiate treatment with immunotherapy

— IHC method (22C3)

— Considered PD-L1-positive if
CPS is 21

+ Other tests, such as MSI and TMB,
can help identify patients with
unresectable or metastatic solid
tumors who may be eligible for
treatment with PD-1/PD-L1 targeted
therapy

1. Han Y ota. Am J Cancer Res. 2020;10:727-742. 2. NCON Cinial Practice Guidelines in Oncology. Cervical Cancer. Version 22024, a
ips vn nocn orgproessionalsphysiian_gls/palcorvical pt PeerView.com

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36. Phase 3 KEYNOTE-826:
1L Pembrolizumab + Chemo + Bevacizumab‘?

Pembrolizumab 200 mg IV Q3W
for up to
+

Paclitaxel + cisplatin or carboplatin IV Q3V

Key Eligibility Criteria
+ Persistent, recurrent, or

metastatic cervical Stratification us odos
cancer not amenable to + Metastatic disease at A
cuxalive treatment diagnosis (yes vs no) Bevacizumab 15 mg/kg IV Q3W
+ No prior systel + PD-L1 CPS (<1 vs 1 to
chemotherapy (prior <10 vs 210) es
radiotherapy and + Planned bevacizumab jacebo
chemoradiotherapy use (yes vs no)

permitted) Paclitaxel + cisplatin or carboplatin
+ ECOG PS0or1 rup

Bevacizumab

+ Dual primary endpoints: OS and PFS per RECIST v1.1 by investigator
+ Secondary endpoints: ORR, DOR, 12-mo PFS, and safety
PROS assessed per EuroQol EQ-5D-5L VAS

+ Exploratory endpoi
1. Colombo N et al. N Engl J Med. 2021:11:38:1856-1867. 2. Monk BJ et al. J Cn One. 2023:5505-5611. PeerView.com

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37. Recent Updates on KEYNOTE-826: Protocol-Specified
Final ORR and DOR: All Analysis Populations’?

a PD-L1 CPS 21

21 us
Se] en
5% me
En u
eo
En calas
S »

:

Fonte mo Mato Chemo
or es

uw
je vi, mo o

so rendre
ie
ye Pembro + chemo + bev
Ps
32
E

‘ine me

ORR, % (95% CI)

Remaining in Response, %

All-Comer

so 562

so] (007715

7

so

20

10

o
Pembro + Chemo” Placebo + Chemo

‘Bev Bev

E Median, mo (range):

so 1813" 10.409)

70 104 (15+ 10407)

so

so

so

S Pembro + chemo à bev

»

d Placebo + Chemo à bev
ELZETIIELZITITZT)

Time, mo

1. Colombo N et al. N Engl Mod, 2021;11;386:1856-1867. 2. Monk BJ e al. J Clin One. 2025;5505-5511,

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PD-L1 CPS 210

: s
Bi: 7
E ©
>
Es
fo
CE
“
°
ombre + Ghemoz "Pacabo. Chano?
eer Sor
2
7 estan, mo ange
is Etre)
it iene
a
ic
sl Poo emo bey
E
;2
Es

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38. KEYNOTE-826: Summary and Conclusions‘?

+ Benefit was observed in all protocol-specified primary analysis populations
— OS: PD-L1 CPS 21 (HR = 0.60), all-comer (HR = 0.63), and CPS 210 (HR = 0.58)
— PFS: PD-L1 CPS 21 (HR = 0.58), all-comer (HR = 0.61), and CPS 210 (HR = 0.52)
+ Safety profile for pembrolizumab + chemotherapy + bevacizumab was manageable
— Observed AEs as expected based on profiles of individual drugs
— No new safety signals after longer follow-up

FDA Approval Indication

In combination with chemotherapy, with or without bevacizumab, for the
2021 full approval? treatment of patients with persistent, recurrent, or metastatic cervical
cancer whose tumors express PD-L1 (CPS 210)

1. Colombo N et al. N Eng! J Med. 2021:11:385:1856-1887. 2. Monk Bet a. J Cin Onc. 2023:5805-5511 eer
3. Keyruda (pembrokzumab) Prescbing Information. ps www accessdataf6a gouérugsatida_docs/abel 2024/1255 1451801 pdt PeerView.com

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39. Phase 3 KEYNOTE-A18: 1L Pembrolizumab + CRT
for High-Risk, Locally Advanced Cervical Cancer!

Cisplatin 40 mg/m? QW

Key Eligibility Criteria is Seen Pembrolizumab
+ FIGO 2014 stage 182-18 Stratification followed by brachytherapy Hf 4090 mg Q6W for

(node-positive disease) + Planned EBRT type = 15 cycles

or FIGO 2014 stage Il- (IMRT or VMAT vs non- Pembrolizumab 200 mg

IVA (either node-positive IMRT or non-VMAT)

or node-negative + Stage at screening

des (stage 182-118 vs IHVA)

+ Planned total

+ RECIST 1.1 measurable en

or nonmeasurable (<70 Gy ve £70 Gy

disease fE020)

+ Treatment naive

+ Primary endpoints: PFS (per RECIST v1.1) by investigator or histopathologic confirmation and OS
+ Secondary endpoints: 24-mo PFS, ORR, patient-reported outcomes, and safety

1 Lorusso D tal. Lance. 2024:403:1341-1950. PeerView.com

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40. KEYNOTE-A18: Clinically Meaningful Benefit Was Shown
With Pembrolizumab + CRT vs CRT Alone’

PFS os
100 i 100 Pembro '
* mo rate 95% Ch: H
# wa 0
Ze 73612029)
La xe
5 En
a2 E
8 HR = 0.70 (95% CI, 0.55-0.89) ¿o
à 9] |P=0.0020 ¿o
go 3
3 Patents Wit Median, mo
ge Event SHC gs
gel 217 NR RNA 2 [Fe 33 WR NEN
E so [Paso 20° NRIRNR) so [Pacte MA RORAR)
9 Juesan totor. mo (argo) 170000 9 [ean tow. mo ange: 1790851
0 3 6 + À 8 8 À à 2 @ os 6 8 À 6 en À 7 » +
Time, mo Time, mo
No, at Risk No, at Risk
SNE aH aS as ds 31 mé 2 151 8 10 1 0
Fe u 0 23 m8 1 ® 2 0 0 °

Si 498 449 402 309 278 214 199 62 12 0

January 2024: FDA approval was granted to pembrolizumab with

chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer?

1. Lorusso D tal. Lancot 2024:403:1341-1350. 2. tps. {da govidrugs/osourcos information approved-drugstéa-approves-pembolizumab-
chemoracitherapy go" 2014-stago-iva-corvcalcancer

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41. KEYNOTE-A18 Safety: TRAE Incidence 220% in Either Arm!

100

1-2 34
Pembro arm fl fl

Placebo arm ll

Incidence, %

Nausea Diamhea WBCCount Neutrophil Vomiting Leukopenia Platelet
Decreased Count Count

Decreased Decreased

Neutropenia

The safety profile for pembrolizumab + chemoradiotherapy was manageable and as expected,
with no negative impact on patient-reported outcomes wi

the addition of pembrolizumab

1 Lorusso Deal. Lance. 2024:403:1341-1950. PeerView.com

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42. What Are The Indications for Immunotherapy
in the Second Line and Beyond?

Pembrolizumab (preferred) for TMB-H, MSI-H, PD-L1+

+ Phase 2 KEYNOTE-158 study!

Nivolumab +
for PD-L1+

+ Phase 1/2 CheckMate 358 trial?

arabe À ot al. J Cin Oncol 2020;38:1-10, 2. Naumann RW et al. J Clin Oncol 2019372825. 2834. PeerView.com

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43. Back to Diana’s Case: Practical Treatment Considerations

for High-

68-year-old woman presented with
postmenopausal bleeding; her last pap was
>10 years ago

Physical examination revealed a large cervical
mass, and subsequent imaging showed tumor
invasion of the bladder

Clinical workup confirmed invasive squamous
cell carcinoma (stage IVA)

Molecular profiling revealed PD-L1 CPS = 20

The patient is il ited on 1L cisplatin/EBRT
followed by brachytherapy + pembrolizumab

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k, Locally Advanced Cervical Cancer

For Discussion

How would you plan to educate the patient
and care team members on drug
dosing/scheduling?

Are there unique safety considerations to
take into account with immune-based therapy

in this setting? Are there overlapping
toxicities with 10 + CRT?

What other AE management principles and
patient-specific factors (eg, barriers to
access, other disparities) should pharmacists
understand?

How would treatment decisions change in the
metastatic setting?

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44. Practical Considerations With Checkpoint Inhibitors
from a Pharmacist’s Perspective

Dosing/Administration
+ Dosing and scheduling considerations

+ Medication access through prior approvals or patient assistance programs
+ Proper supportive care medications as needed

Patient/Caregiver/Care Team Education
+ Educate on more common AEs and have a high level of suspicion for other AEs

+ Encourage patients to call in sooner rather than later
Ensure clinic staff are aware of monitoring parameters and common AEs

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45. Educating Your Patients and Staff About
the Importance of and Access to Clinical Trials

Why is clinical trial participation important?

+ Clinical trials are a key step for translating research into
medicines that can cure illness, slow disease, and improve

QOL for patients

+ Robust participation in clinical trials with diverse enrollment
means a shorter timeline between medical discovery and
patient access to potentially life-changing treatments

q

Social benefit

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Clinical Trial Participation
Offers Dual Benefits for Patients

|. Potential personal benefit: Patients may experience

improved disease outcomes and better health if they

receive otherwise unavailable medical therapies
linical trial participation helps provide
access for patients who may benefit from the new
treatment option by moving a new therapy closer to market

Greater
participation Lack of
= participation
patient =
access to delays and
new higher costs
therapies

Increased patient awareness

Increasing diversity in cl
enrollment is crucial

ssouaieme juoped jo 4927

Providers need to discuss with and offer

clinical trial opportu

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ies to all patients

46. Summary and Parting Thoughts:
What Does This Mean for Pharmacists?

+ Biomarker testing is imperative for all + Educate patients and caregivers

patients — They will have questions as they
+ Different issues may arise with experience these newer modalities
immunotherapy and various — They will ask you questions they
combinations don't ask doctors
— Distinct AE profiles—be prepared > Be prepared

for potential overlapping toxicity,
variable onset timing, and dose
adjustment needs > Know where to direct queries

> Know how to answer

— Prioritize clinical trial enrollment for
all patients with a focus on
increasing diversity

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