Prioritising Patient-Centric Care in Biliary Tract Cancer: Leveraging Immunotherapy Platforms to Overcome Challenges in the Advanced Setting

Chair, Angela Lamarca, MD, PhD, MSc, discusses biliary tract cancer in this CME activity titled “Prioritising Patient-Centric Care in Biliary Tract Cancer: Leveraging Immunotherapy Platforms to Overcome Challenges in the Advanced Setting.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3vTtzwa. CME credit will be available until August 6, 2025.

1. Prioritising Patient-Centric Care

in Biliary Tract Cancer
Leveraging Immunotherapy Platforms
to Overcome Challenges in the Advanced Setting

Angela Lamarca, MD, PhD, MSc

Medical Oncologist

Fundacion Jimenez Diaz University Hospital
Madrid, Spain

2. Introduction

Angela Lamarca, MD, PhD, MSc

Medical Oncologist

Fundacion Jimenez Diaz University Hospital
Madrid, Spain

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

Copyright © 2000-2024, PeerView

3. Our Goals for Today

Improve your understanding of the latest clinical data supporting immune-
based strategies in the upfront management of advanced biliary tract cancer

Enhance your skills to build personalised treatment plans based on the
latest evidence, guideline recommendations, and patient-specific factors in

advanced biliary tract cancer

Provide you with tools to develop team-based strategies to address the
intricacies of care delivery in BTC, including care coordination, patient
engagement, and immune-mediated AE management

Copyright © 2000-:

4. Addressing Unmet Needs
in Biliary Tract Cancers
Where Does Immunotherapy Fit In?

Angela Lamarca, MD, PhD, MSc

Medical Oncologist

Fundacion Jimenez Diaz University Hospital
Madrid, Spain

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

5. Introduction to Philip, a 67-Year-Old Male Patient
With Newly Diagnosed Disease

Philip, aged 67 years, presents with a history
of abdominal pain, nausea, and itchy skin

+ Initial workup revealed CA 19-9 of 20;
albumin: 4.0; total bilirubin: 0.5; BUN: 22;
creatinine: 0.72; WBC 3.5; Hg/Hct: 11.8/36.4;
platelets: 170,000

CT scan showed multiple liver masses, with

the largest measuring 7 x 6.4 cm in the right
hepatic lobe, and multiple enlarged periaortic
lymph nodes

Ultrasound-guided liver mass biopsy showed
poorly differentiated adenocarcinoma

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6. Biliary Cancers

M Intrahepatic—in the liver

Right hepatic duct | Perihilar—near the hilum

Left hepatic duct (where the bile ducts exit the liver)

Common

hepatic duct E Distal extrahepatic—

outside the liver

Cystic duct Common

bile duct

Distal common
bile duct

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7. Ex}

00

20

100

10

am

Rising Incidence of Cholangiocarcinoma!

Age-Adjusted Incidence Rates

2016
Er
me

8

Time, y

1. Jade M et a. Oncologist. 2022:27:874-883,

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(per 100,000 Patient-Years)

COA (n= 40030)

ECC (n= 26821)

foc (n = 13,174)

Survival Probability

080

WOCWECC gg) <0001 82610780
063

CUP WICC SO 6518826
256, <0001 925 v8

CUPYSECC GA <0001 Ba

3 D 75 100 25 150 15 20 25

Time, mo

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8. PeerView.com/EUX827

ESMO Clinical Practice Guidelines for Biliary Tract Cancers!

£ y
Cr]

Cisplatin/gemcital
¡durvalumab [1 A;

ne

FT Molecuarprofing |

‘Adjuvant capecitabine
[UA]

Cisplatin/gemeitabine +
durvalumab ||, A; MCES 4]

: I I J I I 1
Liverdimited HER2neu
10111 mutaton || FGFR21usion | | RAF mutation) | NSt-HEMMR

E E [E rescaris) || escri) | | Tescarıcı ES

CT Free | Dabrafenib/ Trastuzumab/

l'éunane | Mosidenio ; tramatiniy | Pombrolzamas | pertuzumab

SU: |INA¡MCBS2) MCBS 3] | MULA: 1 ii, A]
irinotecan CJ ET

1. Vogel À eta. Ann Oncol 2023:34:127-140 PeerView.com

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9. Current Shortcomings in the Management
of Advanced Biliary Tract Cancers‘?

idvanced CCA found that

Moreover...

Ads

First line Second line Third line
E

er

ma]

Si en.

1. Parikh K otal, ASCO GI 2021. Abstract 347. 2 Valdorrama A et al. ASCO GI 2022. Abstract 398,

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advanced CCA

85% of patients initiated gemcitabine-based
chemotherapy as their first-line treatment

About 46% of patients initiated second-line
treatments, which were predominantly
5-FU-based chemotherapies

Few patients (17%) moved to third line
of treatment

Median time on treatment in the first line
was 3.2 months and in both the second
and third lines was 2.7 months

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10. Important Molecular Markers’

Biomarker-driven management
to improve outcomes

Biospecimen sampling
{tumour blood, urine) —7

Gallbladder carcinoma

en)
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1, Soott Ad etal. J Gin Oncol 2022:40:2716:27%.

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11. : Mutation Load!

Immunotherapy

ewouejon |
snowenbs Bun]
ewoumesouape Bun] |
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apeıb mo} WO! |
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seasoued |
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ewojsejgoinen |
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PlosAu |
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eet

!
IN
7

ry

/

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/

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f

21

“hs
BS

e

a:
(esegeBayy sad suopeynW)

eoue}eresg UOReINW DREUOS

MSI high: 1%

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j
&
$
$
E
+
$
:

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12. Patient Case 1: A 67-Year-Old Male Patient
With Newly Diagnosed Disease

Philip, aged 67 years, presents with a history
of abdominal pain, nausea, and itchy skin

+ Initial workup revealed CA 19-9 of 20;

albumin: 4.0; total bilirubin: 0.5; BUN: 22;
creatinine: 0.72; WBC 3.5; Hg/Hct: 11.8/36.4;
platelets: 170,000
CT scan showed multiple liver masses, with
the largest measuring 7 x 6.4 cm in the right
hepatic lobe, and multiple enlarged periaortic
lymph nodes What patient-specific findings indicate the
Ultrasound-guided liver mass biopsy showed presence of biliary tract cancer?
poorly differentiated adenocarcinoma What additional baseline testing
would you perform to inform subsequent
treatment selection?

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13. Back to Philip’s Case: How Can Patient-Specific Findings
Help to Guide Frontline Treatment Selection?

Philip, aged 67 years, presents with a history of

abdominal pain, nausea, and itchy skin

+ Initial workup revealed CA 19-9 of 20; albumin: 4.0;
total bilirubin: 0.5; BUN: 22; creatinine: 0.72; WBC 3.5;
Hg/Het: 11.8/36.4; platelets: 170,000

CT scan showed multiple liver masses, with the largest

measuring 7 x 6.4 cm in the right hepatic lobe, and
multiple enlarged periaortic lymph nodes

Ultrasound-guided liver mass biopsy showed poorly
differentiated adenocarcinoma

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14. Back to Philip’s Case: How Can Patient-Specific Findings
Help to Guide Frontline Treatment Selection?

Philip, aged 67 years, presents with a history of

abdominal pain, nausea, and itchy skin

+ Initial workup revealed CA 19-9 of 20; albumin: 4.0;
total bilirubin: 0.5; BUN: 22; creatinine: 0.72; WBC 3.5;
Hg/Het: 11.8/36.4; platelets: 170,000

CT scan showed multiple liver masses, with the largest

measuring 7 x 6.4 cm in the right hepatic lobe, and
multiple enlarged periaortic lymph nodes

Ultrasound-guided liver mass biopsy showed poorly
differentiated adenocarcinoma

IHC stain was positive for CK7 and negative for
CDX-2, CK20, p63, TTF-1, and NKX3.1, favoring
ic ICC

ECOG PS1

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15. Review of Immunotherapy Targets and Options!

P A Ant-PDA4 Ant-CTLA4
8 ys cd Anti=PD4 Atezolizumab Ipilimumab
8, Camvelizamab—— Duvalumab Tremelmumab
HR man Dosirimab Envataimab
$5 o Nivolumab
FE Pombraizumab
E Tislelizumab Cadonilimab
É “ec Toripalimab Volrustomig
Teel! a E 117.2 (CDBO/86) Jodetrres
CD27 agonist cd ,
z CDAD ago
Varlilumab- Saga, CDX-1140
APC an there

E car =
= Co133 pcs Mesothelin
¿ Er eo lies
er N nea ag; EGER: Integrin of 0,85
Deseo
°
y Apo E < inhi
Fs Bintrafusp alfa > A DKNO1
‘rumour cat er Tumour cat

1: Lo JH etal. Cancers.2023,15:3912.

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16. 1. ps cinicaias gowet2/showNCT03875235. 2. Oh D-Y eta. Ana Oncol. 2019,30:31.

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Phase 3 TOPAZ-1 Trial: First-Line Immunotherapy +
Chemotherapy in Patients With Advanced Biliary Cancers’?

TOPAZ-1 is a randomised, double-blind, multicenter, global phase 3 study

Key eligibility Duryalumas 17200 mg AM Durvalumab 1,500 mg

Locally advanced or metastatic BTC x Q4W until PD
(ICC, ECC, or GBC)

Previously untreated if unresectable
or metastatic at initial diagnosis
Recurrent disease >6 months after
curative surgery or adjuvant therapy
ECOG PS 0 or 1

Placebo
+ gemcitabine/cisplatin
(upto8 a:

Stratification factors

+ Disease status
— Initially unresectable versus recurrent
Primary tumour location
— ICC vs ECC vs GBC

+ Primary endpoint: OS
» Key secondary endpoints: PFS, ORR, DOR, and safety
+ Exploratory endpoints: efficacy and safety by primary tumour location (ICC vs ECC vs GBC)

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17. Phase 3 TOPAZ-1 Trial: OS Was Significantly Improved
With Durvalumab + Gem/Cis vs Placebo + Gem/Cis!

10

Durvalumab+ Placebo +
Gemici Gem

09 (12341) (a= 344)
08 Median OS, mo (95% CI) 12.9(11.6-141) 113(10.1-125)
12:m0 05 (86% Ch HR (95% Ci), durvalumab +
> 07 54.3% (48.8-59.4) _gemicis vs placebo + gemvcis ld)
z 47.1% (417-523)
3 0s
El 18:m0 08 (86% CI)
8 05 34.8% (29.6-40)
Ê 24.1% (19.6-28.9)
FL) 24:m0 OS (86% Cl)
8 23,6% (18.7289)
03 11.5% (7.6162)
02 Durvalumab + gemvcis
01
o
o 3 6 9 2 1% 18 21 2 27 30 33 36
No. atRisk Time From Randomization, mo
‘Durvalumab + gamin 341 33 34 30 24278 28262 240 227208194 14 160 162 13411798 88 TH 61 52 47 44 0 53 27 21 17 00.8 5 5 1 0
Placebo + gars 344 307 329 316 208 282 260241 22210 17 175158108 12510192 78 €S 0 47 37 29:21 14 119 53332100
1.0h DY etal. ASCO GI 2022, Abstract 98. PeerView.com

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18. TOPAZ-1: Subgroup Analysis of OS!

Hazard Ratio

‘Subgroups (95% Cl),
A patients a 030(0.55-0.97)
<65 la AM 0.80 (0.61-1.04)
fae 265 =e 0.79 (0.60-1.04)
Women — + 0.82 (0.52:108)
Sex Men 1 0.78 (0.60-1.01)
Asian en 0.73 (0.57-0.94)
Be Non-Asian st 0.89 (0.66-1.19)
a Asia EE 0.72 (0.56-0.94)
Region Res of the word nn — 0.89 (0.66-1.19),

AA 68.1:
EcoGrsatbassime 9 m are)
icc — 0.76 (0580.98)
Primary tumourlocation ECC ge 076 (048.118)
sec SÁ 084 (0.85-137)
Inialy unresectable — $ 0.84 (0.59-103)
Dees sans ay un FEN 056 (022080)
es oo 0.49 (0.26.0.88)
Disease classification pos —e—| 0.83 (0.68-1.02)
TAP 21% la a 0.78 (0.61-1.00)
POL expression TAP <li >, 086 (060.123)

o1 os 10 15 20
HR (95% C1)
Favours durvalumab + gemicis Favors placebo + gemicis
1.0n DY et al. ASCO 61 2022. Abstract 378 PeerView.com

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19. Phase 3 TOPAZ-1 Trial: PFS

Median PFS, mo (95% Cl) 72(67-74) 57(5667)
HR (85% Cl) 0.75 (0.63-0.89)
P 001

Probability of PFS

Durvalumab + gemicis

Placebo + gomics
o T T T — Y 1
o 12 15 18 21 24 2 30

No. at Risk Time From Randomization, mo

Durvalumab + gemicis 341 258 189 100 38 25 15 5 o

Placebo + gemicis — 344 255 149 m ” 7 4 o o
Median duration of foto (88% Cl) was 92 (rango, 024) months wih duvalumab + gomies and 6. (range 0.20.4) months wi placabo + gon.
Ss grande color PES P= 481 m
1. Oh DY etal. ASCO 612022. Abstract 37. PeerView.com

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20. TOPAZ-1: Durvalumab + Gem/Cis Demonstrated
a Higher ORR and More Rapid Tumour Responses!

: >
ie ORR’ DOR'
ast Od ati: 1.00 2
(95% 01, 1:11-231: P= 011) z
E) (AAA 3 Remaining in Remaining in
response 23 mo: response 212 mo:
2% 267 E 220% Fe
Ez € 25.3% 15%
5 ar E
ie a H Durvalumab + gemvcis
© 3
5 - Placebo + gemicis
o e r La
Dumatımab + Genis (n= 343)” Piscabo + GamiCia (n= 345) 9 3 6 9 2 5 % À
No. a Risk Time From Randomization, mo
Duvalımab + gemicis 91 7 4 2 13 " s 1
Durvelumab + Ps A
as Placebo + GemiCis
(n=343) Durvalumab + Placebo +
(n = 341) GomiCis
‘ORR, n (%) 91267) 64 (18.7) anon
CR, n (%) 721) 2(06) Median DOR, mo (quartile 1-3) 6.4 (4.6-17.2) 6.2(3.8-9)
PR, n (6) 84 (24.8) 62(18.1) ‘Median time to response, mo
DCR, n (%) 291 (85.3) 284 (82.6) (quartile 1-3) 16133) ra)

+ By investigator assessment using RECIST v1.1 based on pants in the fal analysis set who had messuraio dsxaso at basolno. nas of DOR was based on
patents in o fl analysis et wh had an objective response and measurate Ocaso at bas ino, “Analy of DOR wae based on ol patois in tho hill anaes st ñ
1. Oh DY otal. ASCO GI 2022. Abstract 378 PeerView.com

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21. TOPAZ-1: Summary of AEs and Treatment Exposure’

Durvalumab + Gem/Cis Placebo + Gem/Cis
(n= 342)

Median duration of exposure, mo (range)

Durvalumab/placebo 7.33 (0.1-24.5) 5.77 (0.2-21.5)
Gemcitabine 5.19 (0.1-8.3) 5.03 (0.2-8.6)
Cisplatin 5.13 (0.1-8.3) 4.88 (0.2-8.5)
Event, n (%)

Any AE 336 (99.4) 338 (98.8)
Any TRAE 314 (92.9) 308 (90.1)
Any grade 3/4 AE 256 (75.7) 266 (77.8)
Any grade 3/4 TRAE 212 (62.7) 222 (64.9)
Any serious AE 160 (47.3) 149 (43.6)
Any serious TRAE 53 (18.7) 59 (17.3)
Any AE leading to discontinuation 44 (13) 52 (15.2)
Any TRAE leading to discontinuation 30 (8.9) 39 (11.4)
Any AE leading to death 12 (3.6) 14.(4.1)
Any TRAE leading to death 2(0.6) 1(0.3)

Any

mun

jediated AE 43 (12.

16 (4.7)

‘Includes AEs wth onset dato on or aer the date ofthe frst dose or AES that wersened afte no fest dose. Includes AES oecuing Upto 90 days folowing the date of
tno ast dose or upto the fst subsoquent therapy

1.0h DY etal. ASCO GI 2022. Abstract 378. PeerView.com

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22. KEYNOTE-966: Pembrolizumab + Gem/Cis vs Gem/Cis
Alone in First-Line Advanced and/or Unresectable BTC’

Screening/baseline

+ Histologically confirmed diagnosis of advanced (metastatic) Pembrolizumab (200 mg (
and/or unresectable (locally advanced) BTC (ampullary cancer y +
Dee) Gemetabine (1,009 mom until PD or
ceptable to
Measurable disease based on RECIST v1.1, as determined by z =

the site investigator Cisplatin (25 mg/m? Q3W; up t

No prior systemic therapies

No CNS metastases and/or carcinomatous meningitis

Participants with a history of hepatitis B/C can be enrolled if Placebo (200 mg Q3W; up to 35 cy
they meet study criteria =

Availabilty of archival tumour tissue sample or newly obtained [Gersc#abine (1.000 main Saw Unt GD)
core or excisional biopsy of a tumour lesion iptable toxicity)

Life expectancy >3 months
‘Adequate organ function

Cisplatin Q3W; up to 8 cycles)

Status ‘Active, not recruiting
+ Primary objective: OS Estimated completion date August 31, 2023
+ Secondary objectives: ORR (RECIST v1.1; BICR), DOR (RECIST v1.1; BICR), and PFS (RECIST v1.1; BICR)

+ Safety outcomes: number of patients experiencing >1 AE and discontinuations due to AES

4. Kelley RK ot al Lancet. 2028:401:1853-1865, PeerView.com

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23. KEYNOTE-966: Baseline Characteristics!

Pombro + GemCis Placebo + GemiCis.

Subgroup, n (#4)

(n= 533)
Median age, y (OR) 64 (57-71) 63 (55-70)
Men 220 (53) arm
Race

American Indian or Alaska Nativo 20) 100,
AS 25 (6) 250 (7)
Black or Alcan American 112) ET]
Mute sw 26
Native Hawaiian or other Pacife Itandor 1 o
nite 258 (8) 268 (50)
Messing 36) 122)

242 (45) 244 48)
291 (55) 292 (54)

EcoGPs1 zus) 308 67)

Gatbledder
Intrahopate

Disease status
Locally advanced

Biliary stent or drain
Pror neoacjuvant or adjuvant chemo
Antibiotics within 1 mo of study start
MSA status

Poi cs 21

HBV infection

HCV infection

Pembro + GemiCis,

Placebo + GamiCis

(n= 533) (0= 536)
se (18) 105 (20)
11522) 118.2)
320,60) ER
So) 88 (12)
ECO) 270 88)
EX 4100)
EX 280)
29155) an
sm am
369,68) 365 (68)
1641) 165 (31)
198) 0

4. Kolley RK ot al Lancot 2023:401-1853-1865,

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KEYNOTE-966: Pembrolizumab + Gem/Cis Demonstrated
Significant Overall Survival Improvement at Final Analysis’?

Patients With Ev dian, mo

100 Pembrolizumab + gemicis. 78 42.7 11.5-136)
90 Placebo + gemicis 8 109(99-115)
80 HR (5% C1) 0.83 (072.085)

0034
70

60
50
40
30
20
10

OS, %

Pembrolizumab + gem/cis

Placebo + gem/cis

+ - +
0 3 6 9 12 15 18 21 24 2 30 33 36 39

Time, mo

In December 2023, the European Commission approved the combination for
AL treatment of locally advanced unresectable or metastatic BTC?

1. Kelty RK et al, Lancet 2023:401:1853-1065, 2. tps: cancemetaok comview!pembreizumab-chemo-eceives-european-approvalinistine-ghcancers, -
3. Finn Ret al. ASCO 2024. Abstract 4063. PeerView.com

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25. KEYNOTE-966: Overall Survival Subgroup Analysis!

Site of origin

Disease presentation
ECoG PS

Biliary stentidrain
Smoking status.
Prior chemotherapy

PD-L1 status

4. Finn Rot al ASCO 2024. Abstract 4099.

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265
<65
Women
Men
Asia
Non-Asia
Extrahepatic
Gallbladder
Intrahepatic
Locally advanced
Metastatic

o

1

Yes

No
Never
Former
‘Current
Yes

No

Ps 21
PS «1
indetermir

Patients With Event

Favors Pembro + GemiCis Favors Placebo + Gem/Cis.
Egvörs Penibro + ceils

0:86 (0.75-0.98)
0.90 (0.76-1.08)
0.82 (0.68-0.99)
0.86 (0.72-1.03)
0.87 (0.73-1.04)
0.90 (0.74-1.09)
0.83 (0.70-0.59)
0.97 (072-131)
0.94 (0.72-1.23)
0.81 (0.69-0.96)
0.87 (0.59-1.28)
0.85 (0.74.0.98)
0.92 (0.75-1.11)
0.85 (0.71-1.00)
0.79 (0.49-1.28)
0.87 (076.080)
1.02 (0.67-1.54)
0.92 (0.75-1.13)
0.81 (0.68-0.97)
0.72 (0.46-1.13)
0488 (0.77-1.01)
0.88 (0.75-1.02)
0.88 (0.66-1.17)
0.77 (0.52.1:14)

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26. ASCO 2024: Additional 3-Year Follow-Up Data
From KEYNOTE-966

Patients With Event, % Median OS, mo (95% Ci)

so Porto + ones oo 127 (154136)
e Placebo + gemas 06 1085416)
n [12mo

2? HR = 0.86 (95% Cl, 0.75-0.98)

2 à

6 | 24mo

© « 136mo
o ha
2 fn Pembo + gemicis

Placebo + gemas
EE © @ ©

D 5 6 8 2 © 8 À

Time, mo
No. at Risk
Pembro + gemícis 533 496 430 350 275 217 176 147 131 113 86 64 39 2 15 6 0
Placebo +gemicis 536 483 394 313 236 195 149 125 102 86 63 43 27 2 10 4 0

After an additional 11 months of follow-up, improvement of OS was maintained,

and DOR remained longer in the pembrolizumab arm (8.3 vs 6.9 mo)!

4. Finn Ret al ASCO 2024, Abstract 4093 PeerView.com

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27. KEYNOTE-966: Safety Profiles Remain Consistent
and Comparable Between Treatment Arms!

Subgrou

Any
Treatment related

Grade 3-4 as maximum grade
Treatment related

Led to death
Treatment related

Led to discontinuation of 21 study medication
Treatment related

Led to discontinuation of all study medication
Treatment related

1. Finn Rot al ASCO 2024. Abstract 4099.

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mbro + Gem/Ci

(n = 529)

524 (99.9)
493 (93.2)

420 (79.4)
370 (69.9)

31 (5.9)
8 (1.5)

140 (26.5)
103 (19.5)

35 (6.6)
18 (3.4)

Placebo + Get
(

34)

532 (99.6)
500 (93.6)

399 (74.7)
367 (68.7)

50 (9.4)
3(0.6)

124 (23.2)
82(15.4)

39 (7.3)
14 (26)

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28. Patient-Reported Outcomes Demonstrated That HR-QOL
Was Maintained When Adding Pembrolizumab to Gem/Cis'

Change from Baseline to Week 18
in EORTC QLQ-C30 Scores
Changes Fro

BL to Wook
LS Mean (95% Cl

Difference in
LS Mean (95% ci)

Treatment

Pembro + gemicis| 247

ord 518) (44510049) ae
=
SatisOOL Placebo + gems 251 (2820200)
em (44810-0859)
Pombo + mii 042
Physical (o=518) oa) en) e
ni cebo + gems 7.06 (14210390)
es (9010-574)
Petro + gemas 202
Role (o=518) (95010445) m 7
functioning Placebo + gems 269 (076 106.11)
AE 2200712)

1. Yoo G et al. J ón Oncol. 2023:41:4003 4003.

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Change from Baseline to Week 18
in EORTC QLQ-BIL21 Scores

Ghanges From pitference in

Treatment BL to Week 18, 42 ©
LS Mean ask ci) LS Mean (5% Ci)
Petro + geneis 018
nen 518) (ato 1.42) 028 pS
Placebo + gemein 2 (1.510187)
(n= 516) (14010 1.17)
Peto + gentes su
= 0-56) (18310409) at .
an 1
Placebo + gemein 407 (4.261009)
in 816) (6602218)
Change from Baseline to Week 18
in EQ-5D-5L Visual Analog Scale
E Difference in
imo BLioWencte, Difference
LS Mean ( hese rs
Pembro + gemiis 342
ce esta) (1801) 01 E
= Piacedo + gomiie 356 (SO)
sm) (5200-189)
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29. Phase 2 IMbrave151 Trial: Emerging Evidence
for Frontline Chemoimmunotherapy for Advanced CCA!

Key eli

lity criteria
Aged 218 years

Histologically confirmed metastatic or advanced
unresectable CCA

ECOG PS 0 or 1

No prior systemic therapy for advanced BTC
Measurable lesion, as defined by RECIST v1.1
Adequate hematologic, hepatic, and renal
function

Primary outcome measure: PFS

Atezolizumab + bevacizumab +
gemcitabine/cisplatin

N=162

Atezolizumab +
gemcitabine/cisplatin

Secondary outcome measures: OS, ORR, DOR, DCR, and TTCD

1. Elkhouciy À ASCO Gl 2023. Abstract 401

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30. IMbrave151 Primary Endpoint: Progression-Free Survival!

100

Events, n 0%) 45 (57) 58 (629)
Median PFS, mo (95% C1) 836840) 796234)
20 Sraited HR (95% CI) 0.76 (051-114)

6.mo PFS ato, % (5% GI) 782 (68.8877) 031626730)

* 60
a
i
© 40
Alezo + bev + gemicis (n = 79)
20

Atezo + placebo + gemicis (n = 83)
ot AA 2 + - —

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
No. at Risk ‚Tue; mo,

Atezo + bev+ gemicis 79 75 73 67 Gf 87 86 4 38 18 45 5 5 1 1 NE
‘Nezo + placebo +

gomicis 8 78 72 65 62 OS Si 3 m 18 4 3 NE NE NE

1. EHkhoueiy À ASCO GI 2023. Abstract 481. PeerView.com

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31. Patient Case 2: Frontline Treatment
Selection for Advanced BTC

Philip, aged 67 years, presents with a history of
abdominal pain, nausea, and itchy skin
+ Initial workup revealed CA 19-9 of 20;
albumin: 4.0; total bilirubin: 0.5; BUN: 22; creatinine:
0.72; WBC 3.5; Hg/Het: 11.8/36.4; platelets: 170,000

CT scan showed multiple liver masses, with the largest
measuring 7 x 6.4 cm in the right hepatic lobe, and

multiple enlarged periaortic lymph nodes
differentiated adenocarcinoma
Is this patient a candidate for standard cytotoxic

IHC stain was positive for CK7 and negative for y
CDX-2, CK20, p63, TTF-1, and NKX3.1, favoring therapy or a chemoimmunotherapy regimen?

icc
= Which ICl-based regimens would you consider,
Beenie and how would you select among
validated strategies?

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32. Back to Philip’s Case: Toxicity Management
Considerations for Chemoimmunotherapy Regimens

Baseline scan 11 months later

Philip, aged 67 years, presents with a history of
abdominal pain, nausea, and itchy skin
+ CT scan showed multiple liver masses, with the largest

measuring 7 x 6.4 cm in the right hepatic lobe, and
multiple enlarged periaortic lymph nodes

Ultrasound-guided liver mass biopsy showed poorly
differentiated adenocarcinoma

IHC stain was positive for CK7 and negative for CDX-
2, CK20, p63, TTF-1, and NKX3.1, favoring
intrahepatic ICC

+ ECOGPS1
The patient initiates upfront therapy with
pembrolizumab + gemcitabine/cisplatin

+ Upon follow-up, the patient's hemoglobin is found
to be 9 gldL.

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33. Back to Philip’s Case: Toxicity Management
Considerations for Chemoimmunotherapy Regimens

Baseline scan 11 months later

Philip, aged 67 years, presents with a history of

abdominal pain, nausea, and itchy skin

+ CT scan showed multiple liver masses, with the largest
measuring 7 x 6.4 cm in the right hepatic lobe, and
multiple enlarged periaortic lymph nodes

Ultrasound-guided liver mass biopsy showed poorly
differentiated adenocarcinoma

IHC stain was positive for CK7 and negative for CDX-

e aan LL Recommendatión |
intrahepatic ICC Recommendation

ECOG PS 1 Reduce the dose or delay chemotherapy to allow
recovery of myelosuppression

The patient initiates upfront therapy with

pembrolizumab + gemcitabinelcisplatin

+ Upon follow-up, the patient's hemoglobin is found
to be 9 gldL.

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34. What Are the Most Common AEs of PD-1/PD-L1 Therapy?!

Encephalitis, aseptic mening

Hypophyete— |
a EB.

‘Thyroiditis, patrol, —\ >
‘hyperthyroidism,

Paeumonits 7 o vigo.

Thrombocytopenia,

¡Pa
Bl

lly related to ti

‘occur throughout the cout

1. Postow MA tal N Engl J Mod. 2018:378:158-168,

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Adverse Event

‘Skin changes
(eg, redness, itching)

Hypothyroidism
Hyperthyroidism
Ci
Hepatitis

Nephritis

Pneumonitis
Hypophysitis

Type 1 diabetes mellitus
Pancreatitis

Myositis

Myocarditis,

Encephalitis

ated Frequenc:

40-50

20-30
5-10
10-30
5-10
5-10
5-10
1-3
123
1-3
1-3
1-3
1-2

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35. Patterns and Duration of Common Immune-Related AEs"

CTLA-4 Inhibitors

PD-1/PD-L1 Inhibitors

Toxicity Grade

o 4 6 6 0 2 à > o 4 6 8 0 & % >30
‘Treatment Duration, wk Treatment Duration, wk

PD-1/PD-L1 + CTLA-4 Inhibitors

3
E Endocrinopatny
ÿ
2
3
y

Nephitis
o 4 6 8 © 2 ET
1. Martins F et al Nat Rov Cin Oncol 2018:16:563-580. Treatment Duration, wk

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36. ESMO Guidelines on General Toxicity Management:
Principles for Immunotherapy’

irAE management generally consists of four
‘sequential steps

1. Diagnosis and grading of irAES Managed in outpatient! Generally requires

community setting hospital admission
2. Ruling out differential diagnoses and pre- < = >

immunosuppression workup

Roferral to special
Strong immune suppres

3. Selecting the appropriate immunosuppression
strategy for grade 22 events

ont

2
gf
+ The lowest effective CS dose should be ge = =
prescribed for the shortest possible duration, E || Symptomatic and supportive therapy

which, in general, will be several weeks for

+ CS therapy tapering or discontinuation only on Mild Vey severe)
medical advice
+ Lifestyle adaptations to minimise the risk of
CS-induced AEs
1.Haanan J etal Ann Oncol 2022:33:1217-1238, PeerView.com

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37. Patient Case 3: Toxicity Management Considerations
for Chemoimmunotherapy Regimens

Baseline scan 11 months later

Philip, aged 67 years, presents with a history of

abdominal pain, nausea, and itchy skin

+ CT scan showed multiple liver masses, with the largest
measuring 7 x 6.4 cm in the right hepatic lobe, and
multiple enlarged periaortic lymph nodes

Ultrasound-guided liver mass biopsy showed poorly
differentiated adenocarcinoma

IHC stain was positive for CK7 and negative for CDX-

e are Discusión |
intrahepatic ICC Discussion

+ ECOGPS1 How should the care team manage
myelosuppression in this patient?

The patient initiates upfront therapy with
pembrolzumab + gemertabine cteplatin What other irAEs should the care team be
+» Upon follow-up, the patients hemoglobin is found prepared to monitorimanage when integrating

to be 9 gldL.

chemoimmunotherapy regimens?

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38. Introduction to Christina, a 60-Year-Old Female Patient
Progressing on First-Line Chemotherapy

Christina presented with a history of abdominal pain, fatigue, and
unintentional weight loss

Initial workup revealed total bilirubin: 1.2 mg/dL; AST: 56 units/mL;
ALT: 67 units/mL; platelets: 105,000/mcL

Imaging confirmed bilobar hepatic disease with pulmonary metastases
ECOG PS 1
Patient treated with upfront gemcitabine/cisplatin; progression after 4 months

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39. Second-Line Experience With Pembrolizumab for Biliary Cancer!

+ KEYNOTE-028: phase 1b biomarker-selected basket

+ KEYNOTE-158: phase 2 unselected multicohort study

+ Most heavily pretreated patients
+ Pembrolizumab was well tolerated

— 18% had immune-related AES

— 6% were grade 3; no grade 4/5 AES

+ Caveals: location of biliary cancer was
not collected

+ Atleast 1 patient in KEYNOTE-028 was MSI-H;
others were missing MSI status

+ Assays for PD-L1 differed between the two trials
- KEYNOTE-028: prototype assay
- KEYNOTE-158: CPS >1 using IHC 2203

1. Pina-Paul SA ota. nt J Concor.2020;147:2190-2198,

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Change From Baseline, %

in Target Lesions by RECIST 1.1, %

100 POLA positive KEYNOTE-158)
1 PD-L1 negative (KEYNOTE-158)
00 1 POLI NE (KEYNOTE: 188)
co ANUN 1m PD-L1 positive (KEYNOTE-028)
«o |
AIT 20% tumour increase

2

o
20
+ 30% tumour reduction
0
80 'ORR KN-028: 13 (2.8-33.6); DOR >24 mo: 66.7

ORR KN-158: 5.8 (2.1-12.1); DOR >24 mo: 50

400

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40. KEYNOTE-158: Updated Analysis Showed Meaningful Activity
and Durable Responses for Pretreated MSI-H/dMMR BTC’

“

x 100: smal à cn 5,
zo intntne Orafan | Bar Tract Paneretic
& 60 (229 ) 2)
8 «0.
32 ‘ORR, % 485 a 48 333 102
a (05% cp 62510) (178474) @78687) (156553) (62403)
gx Best objective
30 response, (2)
Bs ES am «es m aa | sm | 169
ia PR 2938 sem sc 508) | sers | 3000
8 so won zum 7a) 263 | 905 | 3035
400 Patients Po 19279) 16667 seo 12460 | 806%) | 2664)
mDOR,mo NR NR NR NR ns NR
Pr ange) 291047.) (63105119 (214104130) (42104350) (6240.59) |(e:110245+)
ES PFS, mo 1 32 24 22 42 24
E 185% €) ws eo am 2062 | eres | 0934
n
zo PFS rato
xe e EN) 205 401 22 127 NR
ae mOS, me NR 1" NR 236 194 37
2]; en Buch G24NR) Wi zn mon) | SNR) | 2198)
Bl mere 05 rate
, Bee, 021 us sr 428 203 21
ELZEIITETZILIZTTZ.
Time, mo
4. Malo Metal. Ann Oncol. 2022:33:929-938. PeerView.com

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41. Phase 2 LEAP-005: Lenvatinib + Pembrolizumab
for Previously Treated Biliary Cancers!

N=31 Percentage Change From Baseline in Target Lesion Size» Progesson-Free Survival!
ORR, %(95%C!) 10(220) “e Heron ie
DCR", % (95% CI) 68(49-83) 5 E
22
CR o Almen 1
PR 3000? E |
sD 18 (58) a a E 2
PD 7 (23) 20% men 5 à ; :
Nonevaluable® 2(6)
No assessment” 16) Overall Survival
‘Median DOR, mo 53 ”
(range) (22.1-6.2) +
In patients with advanced biliary cancers who did not respond cl
to one prior line of therapy, lenvatinib + pembrolizumab Te ——
demonstrated encouraging efficacy and manageable toxicity man Tine, me

+ Don as best overall response of GR. PR. o SD. Al ospondors ha a POLL! GPS 21. Patent ha postbaslne imaging, andthe best ovrl responsa was
determined o be nonevaluabe per RECIST vi 1. * Patent had no pastoaseine imaging.» Paton with westment ongoing." PPS por REGIST vi.1 by BIER. ñ
1 .Vilenueva Let al ASCO 2021. Abstract 4080, PeerView.com

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42. Other Ongoing Trials With Immunotherapy’

Drug Phase NCT
Nivolumab monotherapy in the second-line setting 2 NCT02829918
Durvalumab + SNDX-6532 2 NCT04301778
Sitravatinib + tislelizumab 2 NCT04727996
Bispecific antibodies + standard agents E NCT05775159
Durvalumab + tremelimumab + RT in the second-line setting 2 NCT03482102
Nivolumab + rucaparib in the second-line setting 2: NCT03639935
Durvalumab + tremelimumab + paclitaxel (IMMUNO-BIL) 2 NCT03704480
Nal-irinotecan + nivolumab in the second-line setting 1/2 NCT03785873

1. hipsfinicatals. gov. PeerView.com

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43. Patient Case 4: A 60-Year-Old Female Patient
Progressing on First-Line Chemotherapy

Discussion

Christina presented with a history of Given baseline testing is incomplete, what

abdominal pain, fatigue, and unintentional oe >
weight loss additional testing would you order?

+ Initial workup revealed total bilirubin: How would you approach second-line
1.2 mg/dL; AST: 56 units/mL; ALT: 67 units/mL; treatment selection for this patient?
platelets: 105,000/mcL

Imaging confirmed bilobar hepatic disease with
pulmonary metastases

ECOG PS 1

Patient treated with upfront
gemcitabine/cisplatin; progression after
4 months

Further evaluation reveals MSI-H/dMMR status

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44. Conclusions

Angela Lamarca, MD, PhD, MSc

Medical Oncologist

Fundacion Jimenez Diaz University Hospital
Madrid, Spain

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45. Conclusions

+ Immune checkpoint inhibitors have shown promising activity as monotherapy or
in combinations, which are being validated in additional clinical studies

+ Chemoimmunotherapy is the preferred primary treatment choice for unresectable and
metastatic BTCs, as supported by the phase 3 TOPAZ-1 and KEYNOTE-966 trials

+ Biliary cancers are genetically heterogeneous, with many potentially targetable
genetic alterations

+ Immune-based therapy remains investigational in the 2L setting (with the exception of
pembrolizumab for MSI-H/dMMR tumours)

+ Participating in a clinical trial is highly encouraged to identify effective treatment
for patients with biliary cancers

+ The next cohort of trials will include bispecific antibodies and CAR-T therapies as
new potential treatment options

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