Playing the Right Sequence in mCRC: Practical Strategies for Integrating Multi-Kinase Inhibitors in Later Lines of Therapy

Chair Tanios Bekaii-Saab, MD, discusses colorectal cancer in this CME/NCPD/CPE/AAPA/IPCE activity titled “Playing the Right Sequence in mCRC: Practical Strategies for Integrating Multi-Kinase Inhibitors in Later Lines of Therapy.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3YV8koW. CME/NCPD/CPE/AAPA/IPCE credit will be available until August 28, 2026.

1. Playing the Right Sequence in mCRC
Practical Strategies for Integrating
Multi-Kinase Inhibitors in Later Lines of Therapy

Tanios Bekaii-Saab, MD

David F. and Margaret T. Grohne Professor

of Novel Therapeutics for Cancer Research |

Chair and Consultant, Division of Hematology and Medical Oncology
Professor, Mayo Clinic College of Medicine and Science

Mayo Clinic

Phoenix, Arizona

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

Copyright © 2000-2025, PeerView

2. Our Goals for Today

Augment your knowledge of the latest evidence and guideline
recommendations for sequential TKI approaches in mCRC

Enhance your skills for formulating individualized, sequential

treatment plans that consider the latest clinical evidence and
patient-specific factors

Equip you with strategies to address practical aspects of care
with TKls, including managing TRAEs, dosing considerations,
and shared decision-making with patients

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3. Module 1

Collaborating to Effectively Treat mCRC
Real-World Solutions to Address Unmet Needs

Copyright © 2000

4. Why Are We Here?
Exploring Unmet Needs in Advanced/Metastatic CRC

- Only 74% of mCRC patients receive second-line treatment,
only 63% receive third-line treatment, and only 45.9% receive
After First-Line fourth-line treatment!
Treatment - Recycling of chemotherapy and biologics in the second- and
subsequent-line settings is common and occurs more frequently than
switching to a drug regimen with an alternative mechanism of action?

- The expectations in later-line treatment focus on patient preference,
Management tolerability, and QOL?

in nes - Various dosing regimens have been used to reduce AEs and improve

of Treatment QOL, but efficacy benefits have not been demonstrated with these
dosing modifications*

1: Tapetes Metal. Gin Gaec Cancer 2017: 1637276, 2 Food W et al. J Cin Oncol 202020supp4)56, 9. ATED ela. Ann Oral 201820035850. Dee V/i ew
4. Bekai-Saab TS el al. Lancet Oncol, 2019.20:1070-1082. 'eerView

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5. MSI-H and/or dMMR: co amplification a MET amplification: NTRK fusion:

3.5% to 5% corer 3% 1% P 2% Mi
EGFR: ERBB2.
EGFR) res) || ERBB2 | HER3
— ei:
HP2CSHC

Le
SOS GR!
Y
KRAS-NRAS wild type: 45% to 55%
ER ms
> BRAF WE. 5% to 9%
u BRAF non-V600E: 1% to 2%

es 2

| Bando Het al. Nat Rev Gastrcentorol Hepatol 2023.20 308-322.

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6. However Alterations Only Present in 10% to 20% of Cases!

Clinical Outcomes
With Select Targeted Therapies

Actionable Targets
in Metastatic CRC

2 Pembrolizumab
2 Nivolumab
\ volumab + ipmumab
a ren vaca
# m0» o
a
Trastuzumab ¥ @ Larotrectinib
KRASINRAS E rip derustecan
ex 2-4 mutation 54 Encorafenib + binimetinib + cetuximab
3 Paritumuma
3 abraten + rametinb + pantumumad
= Dabrafenib + @Entrectinb
2 | panitumumab
0
0 10 20 30 40 50 60
ORR, %
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1. Steller J etl. JAMA Oncol, 2022:8:760-768.

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7. NCCN: Subsequent-Line Choices Are Informed

History and Genetic/Molecular Features!

>

FOLFIRI or irinotecan

FOLFIRI + bevacizumab (preferred)

or ziv-aflibercept or ramucirumab For disease that

Irinotecan + bevacizumab (preferred) has progressed
or ziv-aflibercept or ramucirumab through all
Previous or available regimens
PSE —| 15 KRAS/VRAS/BRAF WT + Fruquintinib
erapy without . ER fenib
irinotecan FOLFIRI + (cetuximab or egoral
panitumumab) + Trifluridine +

(Cetuximab or panitumumab) +
irinotecan

tipiracil (TAS-102)
+ bevacizumab

or

Biomarker-directed therapy

1. NCON Cinca Practice Guidelines in Oncology. Colon Cancer. Version 4.2025. hip. or/roessonaslohicn. taco pl. PeerView

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8. Goals for the Team

Work collaboratively to ensure:
v Patients get the right treatment
Patient for their disease
Sar 1eam Y Toxicities are managed
v Appropriate dose adjustments
are made as needed
v Patients/care partners receive

Nurse adequate education
Practitioners

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9. red Decision-Making Is Critica

Colorectal Cancer Alliance Resources to Share With Patients

Download the
Practice Aid!

qG go Our Strategic Goals

alliance

ee Bn AA
pa ese emery rte \
en Ye
Ihnen. DE. e Asan aac or enden suple | Intuence 00
A A OS
a 5

ae Learn more at colorectalcancer.org

3 Patient navigation/Helpline
= Clinical trials and CRC

E Take our free screening quiz

Yearlong Reach & Impact

133K emai subscribers

annual ist cross our usted patient and
2-9M Srareness focused website

226K social media followers
78 media impressions raising awareness
820M Nielsen audience TV and radio PSA
13.4K online community members
110K patients received expert navigation
12K Walk to End Colon Cancer participants
2K active volunteers nationwide

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10. Module 2
Revising Our Treatment Approach in mCRC

Expert Guidance on Adequately Sequencing Multi-Kinase
Inhibitors in Advanced Disease

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11. Introduction to Mitchell, A Pati
After Two Treatment Regimens

Mitchell, a 62-year-old man presenting with
mCRC and good organ function

At initial presentation, ECOG PS 1

KRAS mutated (non-G12C)
First line: FOLFOX + bevacizumab

After 5 months, switched to capecitabine
+ bevacizumab How would you approach
Second line: FOLFIRI + bevacizumab Sequencing tnereby for thls ao
Let's review the evidence

in this next segment...

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12. Many Drivers for First-Line Treatment
Are Also Valid in Later Lines of Therapy!

Tumor Characteristics Treatment

Characteristics

« Clinical presentation + Age + Toxicity profile
— Tumor burden + Performance status + Flexibility of treatment
- Tumor localization | |- Organ function administration
+ Tumor biology * Comorbidities + Socioeconomic factors
+ RAS, BRAF, and » Attitude, expectations, | |* QOL
HER2 status and preference
+ MSI status | |
Patient and treatment characteristics become even more relevant in later lines
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1. Van Cutsem E et al. Ann Oncol 2016:27.1388-1422

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13. Regorafenib

Placebo

0 2 4 6 8 10 12 14
Time After Randomization, mo

Regorafenib
505)
OS, mo 64

Regorafenib

2 4 6 3 10 12
Time After Randomization, mo

PFS, mo 19 17

1. Grothey A tal. Lancet 2013:381:303:312

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HR (95% Cl) P
0.77 (0.64-0.94) 0052
0.49 (0.42-0.58) <.0001
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14. Phase 3 RECOURS
Improvement

nal Results Showed
02 Compared With Placebo!

100 TAS.

2 Placebo

(n= 534) (n = 266)
& Median OS, mo 3 53
HR (85% Cl) 0.68 (0.58-0.81); P < .001

e la
o
© 40
20 TAS-102
Placebo
0
o 3 6 9 12 15 18
No at Risk Time Since Randomization, mo
TAS-102 534 459 294 137 64 23 7
Placebo 266 198 107 47 24 9 3
1. Mayor Rie aN Engl Y Med 2015:3721900-191. PeerView

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15. Proposed Treatment Algorithm for Advanced Lines!

Third Line Fourth Line
8 | mcRc with or without oncogenic drivers
8
5 TAS-102 = Regorafenib
3 Regorafenib = —> TAS-102
e er Osoc
1. Lenard 8, reanono F, Mat Ro Gestoentero! Hepa. 20242178: PeerView

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16. Phase 3 SUNLIGHT: The Addition of Bevacizumab to TAS-10;

Led to Significant Improvements in OS and PFS"

os PFS
HR for death = 0.61 _ HR for disease progression
(95% Cl, 0.49-0.77) hal or death = 0.44
P<.001 =

TAS-102 +

peeizumab, TAS-102 +

bevacizumab

Patients, %
88883

TAS-102

01234567 8 9 10111213 14 15 16 17 18 1920 0123456

Patients, %
s35s#ssszsss

7 8 9 10 11 12 13 14 15 16 17 18
Time, mo

2a 242 160 178 169 108 99 80 70 61 de do 2 1805 7 4 2 0
248 230 147 109 74 65 36 2 19 12 8 6 2 2 1 1 0 0 ©

Nat Risk oat Risk
PES, nun ow ea or ws 2 0 0 Mee
cine Deven
TASACZ 248 242 790 205 186 163 143 120 108 GS 85 76 63 44 2% 16.10 5 2 1 0 TASIOZ

FDA approved

August 2023?
Prat Ue Ente 229380168 17.2, Monn govt pra antun spot nn an spnctrecumas- De 0 Vi ew.

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17. Proposed Treatment Algorithm for

Third Line Fourth Line
8 mCRC with or without oncogenic drivers
8
5 TAS-102 => Regorafenib
Regorafenib = —> TAS-102
5 oe O soc
mCRC with no oncogenic drivers O SUNLIGHT
TAS-102 + bevacizumab
2
3
8
&
1. Lonard, Pieanono F Nat Rov Gastwentrel Hepatol, 02421767. PeerView

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18. VEGF-B VEGF-A VEGF-E VEGF-CID

EEE OSU rat,

rice
|
ne )
! mex
ET Ce m
x ES x

+ y

1. Mis Nono cancer research netnock com 2023/12/14 ruquintin à seleclie vegh 2-3 nor for colorela cancer teseareh.

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19. Phase 3 FRESCO-2: Fruquintinib Demonstrated Improved

OS and PFS in Refractory mCRC (ITT Population)!

os

Fruquintinib + Placebo + BSC

BSC (n = 461) (n= 230)
Median follow-up, mo.
Events, n (%)
Stratified P (log-rank)
Stratified HR (95% Cl)
Median OS, mo (95% Cl)
Median OS difference, mo

317 (68.8) 173 (75.2)
<001

0.662 (0.549-0.800)
74(67-82) 4.8(4.0-5.8)
26

Subsequent anticancer medication was

PFS
Fruquintinib Placebo
Events, n/N (%) 392/461 (85) 213/230 (92.6)
Stratified log-ranked P <.001
Stratified HR (95% Cl) 0.321 (0.267-0.386)
Median PFS, mo (95% Cl) 3.7(3.5-38) — 1.8(1.8-1.9)
mPFS difference, mo 19

> balanced between the two arms: Bo

3” 29.4% fruquintinib vs 34.3% placebo 3

So Bo

2 2

Lu Lo

5 7 Fruquintinib + BSC

Oo” eo

Wie cee Ñ Placebo + BSC

a Time Since Randomization, mo Time Since Randomization, mo
+. Daa At Lancet 2028402415, PeerView

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20. FRESCO-2: Fruquintinib Was Effective and Tolerable
Regardless of Prior Treatment Sequence’

Events, n/N
HR (95% Cl)
Fruquintinib | Placebo
TAS-102 and
regorafenib-naive 0.652 (0.512-0.829) 188/278

Median OS, mo (95% CI)
Fruquintinib

Placebo

109/138 9.3(8.2-10.5) 6.6 (5.9-8.1)
TAS-102 only 0.723 (0.557-0.938) 165/240 88/121 7767-85) 5.1 (4.0-6.3)
Regorafenib only 0.772 (0.379-1.573) 25/40 12/18 10.2(6.1-11.6) 8.2 (3.7-14.4)
TAS-102 > regorafenib 0.532 (0.353-0.802) 66/95 37/44 66(49-7.8) 3.3(2.8-5.4)
Regorafenib > TAS-102 0.666 (0.432-1.025) 60/84 36/45 8.5(6.3-10.5) 4.8(3.4-6.7)

01 05 1 10
Favors Fruquintinib Favors Placebo

AAA

el

1. BekaiiSaab TS et al, ASCO 2024, Abstract 2579,

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21. Proposed Trea t Algorithm for Advanced Lines!

Third Line Fourth Line Fifth Line
—_—_—_ |
8 mCRC with or without oncogenic drivers
8
5 TAS-102 => Regorafenib
8 Regorafenib > TAS-102 Dsoc
mCRC with no oncogenic drivers O SUNLIGHT
E FrEscO-2
TAS-102 + bevacizumab —> Fruquintinib (regorafenib)— Regorafenib (fruquintinib) EJ codeBreak 300
8 mCRC with oncogenic drivers (eg, KRASS'2¢ mutation)
8
¿| Tas-102+ bevacizumab—> ¡gee AS Fruquintinib (regorafenib)
E
Targeted therapy» "mar + TAS-102
(eg, sotorasib + Bates + Fruquintinib
panitumumab) en + Regorafenib
1. Lonard, Pieanono F. Nat Rov Gastwenterel Hapao. 02421767. PeerView

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22. Comparison of Modern Studies Evaluating Regorafen

02 + Bev, and Fruqu

Regorafenib

SUNLIGHT

5.593 Prior Bev)

FRESCO 2

100% BEV
100% BEV 100% EGFR mAbs

Prior biologics (72%)
100% EGFR mAbs 100% Rego or TAS-
102 27? EGFR

TAS-102

REGO REGO 160 FRUQ BSC+PL TAS-102

Subgroups = = 2 a + Bev =
(n=54) (m=62) (n=136) (n=68) (247g) (N= 17)
Prior lines
<2 0% 0% 0% 0% 100%
>3 100% 100% 100% 100% °
Median OS, mo 10 6 74 48
4. psc gov.

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Fruquintinib TAS-102 + Bev

SUNLIGHT
No Prior Bev)

Prior Bevacizumab [No Prior Bevacizumab

(28%)
22 EGFR

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23. Patient Case Revisited: A Patient With mCRC Progressing
After Two Treatment Regimens

Mitchell, a 62-year-old man presenting
with mCRC and good organ function

At initial presentation, ECOG PS 1
KRAS mutated (non-G12C)
First line: FOLFOX + bevacizumab
After 5 months, switched to

Case Discussion

+ Based on current evidence
and guideline

recommendations, what
treatment option would you
consider next?

capecitabine + bevacizumab
Second line: FOLFIRI + bevacizumab

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24. : Sequential Treatment With Regorafenib + TAS-102 + Bev
in Refractory mCRC in Community Clinical Practice in The USA?

Patient selection period (January 2015 to September 2022)
Baseline period (26 months prior to index date)

Inclusion criteria Index dates
+ Patients with mCRC aged 218 years

at diagnosis
+ Patients treated sequentially with

regorafenib and TAS-102 + bev following
mCRC diagnosis Follow-up (for a minimum of 3 months)

Exclusion criteria until the earliest death, last date of activity,
+ Patients with a GIST, HCC or other primary or end of study

cancer diagnosis within 6 months prior to

index date (excluding non-melanoma

skin cancers)
+ Clinical trial enrolment during the

study period

"Date raton ol retment win e patent seccion ers on or ter January 1,201) Mew
{Abn Det al. Cancers (Base) 2025,17:989 2, Geka Saab Tel al ESMO 2023, Abavact SP. PeerView

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25. Appeared to Have a Longer Time to Discontinuation (TTD)!

R-T (n= 167) T-R(n=176) R-T(n=87) T-R (n= 107)

Time to discontinuation,

median mo (IQR) 8.3 (5.6-12.2) 7.2(5.2-10.3) 8.2(6.0-11.7) 7.7 (6.0-10.0)
Median (KM method), 87 8.1 8.5 79
months (95% Cl) (7.8-9.8) (6.9-9.0) (7.3-10.0) (7.3-9.1)
Unadjusted HR (R-T vs T-R) 0.91 (0.73-1.14) 0.86 (0.63-1.16)
Adjusted HR (R-T vs T-R)* 1.03 (0.79-1.33) 0.84 (0.58-1.23)

std for age, sex. ECOG PS, KRAS mutation sas, pr tgets reiments (a EGFR or ev) and lage a ital cannes. jew
‘nbn Dell Cancers (Bee), 2025.17.00. PeerView

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26. STAR-T: Patients Treated With Sequential R-T vs T-R

May Have Longer Overall Survival!

arts 3L OS for R-T and T-R eum 4L OS for R-T and T-R
2 2
© ©
£ 8
Si Den
ing ira
© E
2 2
5 5
Boo Bow
® 2
a ö
q” ar
2 2
2 2
5 3
Do Bo
y y ES 5 y % i a ry > y E
Time, mo Time, mo
ESTATE
Follow-up time, median mo (IQR) 11.2(68-186) — 10.1(65-165) —Follow-uptime, median mo (OR) 10.4(7.4-14.9) 9.8 (69-148)
Median (KM method), mo (95% Cl) 13.1(110151) 11.5(104-137) Median (KM method), mo (95% Cl) 11.6(9.6-132) 103(8.9-126)
Unadjusted HR (R-T vs T-R) (95% CI) 0.94 (0.74-1.19) ‘Unadjusted HR (R-T vs T-R) (95% Cl) 0.86 (0.63-1.18)
Adjusted HR (R-T vs T-R) (95% Cl) 0.99 075-129) Adjusted HR (R-T vs T.R) (95% CI 0.90 (061131
1. Am D tal Cancers (Base), 20257369 PeerView

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27. Module 3
Team-Based Personalized Care in mCRC
Addressing the Practicalities of Treatment Delivery With

Multi-Kinase Inhibitors

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28. Patient Case Continued: A Patient With mCRC Progressi
After Two Treatment Regimens

Mitchell, a 62-year-old man presenting
with mCRC and good organ function

At initial presentation, ECOG PS 1
KRAS mutated (non-G12C)
First line: FOLFOX + bevacizumab

After 5 months, switched to capecitabine +
bevacizumab

Second line: FOLFIRI + bevacizumab

The patient is initiated on third-line TKI
(regorafenib)

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What findings can we apply
from recent studies
pertaining to treatment

dosing/scheduling?

Let's discuss...

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29. Reg

Dose: regorafenib 160 mg once daily on days 1-21

fenib Dosing Was Ori

ally Based o

e CORRECT Trial!

Any grade Grade 3 Grade 4 grade Grade 3 Grade 4

0

1 0

0 3 0

Voice changes 29 <1 0 6 0 0

Hypertension 28 7 0 6 1 0

Oral mucositis 27 3 0 4 o 0

Rash/desquamation 26 6 0 4 0 0

Nausea 14 <1 0 1 0 0

Weight loss 14 0 0 2 o 0

Thrombocytopenia 13 3 <1 2 <1 0

Fever 10 1 0 3 0 0
1. Grothey À et al Lancet 2019;381:209-312. PeerView

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30. Escalating Dosing
Week of C1 With an
A: 80 mg/day increasing to 160 mg/day MN Dose Opt ion
(preemptive clobetasol) Tee
A2: 80 mg/day increasing to 160 mg/day WG y 20e)
(reactive clobetasol) 3 End dose C1 160 mg

4 Off

Key Inclusion
Criteı

+ Patients with

previously br dl d

treated mCRC Standard Dosing Primary endpoint: proportion of
+ ECOG PS 0/1 patients who complete 2 cycles
+ (N=116) and initiate third cycle

(composite endpoint integrating
safety and tolerability)

Secondary endpoints: QOL,

cumulative dose, dose intensity,

OS, PFS, TTP
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1. Bekaii-Saab TS et al. Lancet Oncol. 2019,20:1070-1082,

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31. Percentage of Patients
Starting Cycle 3

P=.043

43

Patients, %
sas

a

47% PD

oad

Escalating Dose

1. Bekai-Saab TS et al. Lance! Oncol. 2019,20:1070-1082,

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Standard Dose

Overall Survival
HR: 0.72 (95% CI: 0.47-1.10);
= 12)

= 80

7 Dose-escalation group
¿o (arm A, n = 54)

é Median, mo (95% Cl):
= 40 9.8 (7.5-11.9)

E Standard-dose

ó

group (arm B, n = 62)
Median, mo (95% Cl):
6.0 (4.9-10.2)

T T TT ET 1
0 3 6 9 12 15 18 21 24

Time, mo

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32. Escalation Group (n = 54)

Daily regorafenib dose received
Omg

1180 mg

1120 mg

1160 mg

Patients
Patients

Week 1 Week 2 Week 3 Week 1 Week 2 Week 3 Week 1 Week 1 Week 2 Week 3 Week 1 Week 2 Week 3 Week 1

1. Beka Sa TS el, Lancet Oncol 201920:1070-1082, PeerView

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33. ReDOS: Dose-Escalation Approac
Was More Tolerable and Maintained QO!

Dose escalation was associated with comparable activity and a lower incidence of AEs

Escalating Dose (n = 54) Standard Dose (n = 62)
Grade 3 Grade 4 Grade 3 Grade 4
Fatigue 11 (18)

Grade 3/4 AEs Occurring in 24% of Patients, n (%)

PPES 10 (16) o
Abdominal pain 416) o
Hypertension 9(15) 0
Hyponatremia 2(4) 12) 4 (6) 12)
Bilirubin increased 2(4) o 5 (8) o

Alkaline phosphatase increased 36) o 1(2) 12

AST increased 1(2) o 46) 0

Colonic obstruction 3(6) 0 0 0
Dehydration o o 5 (8) o
Dyspnea 1(2) 1(2) 4.6) 0
Lymphocyte count decreased 4(7) o o o
Maculopapular rash 0 o 36) 0

1. Beta Saab TS eL al Lancet Oncol 201920:1070-1082 PeerView

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34. Overall QOL

4
Time, wk

1. Bekaii-Saab TS et al Lancet Oncol. 2019,20:1070-1082,

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No deterioration
in QOL in the
dose-escalation arm

A decrease in QOL at

the time point when
one would expect
maximal grade of AEs
(at 2 weeks)

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35. Patient Case

Mitchell, a 62-year-old man presenting with
mCRC and good organ function

At initial presentation, ECOG PS 1
KRAS mutated (non-G12C)

First line: FOLFOX + bevacizumab

After 5 months, switched to capecitabine
+ bevacizumab

Second line: FOLFIRI + bevacizumab

The patient is initiated on third-line TKI
(regorafenib)

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Pharmacist explains regorafenib dosing
schedule (eg, 80 mg - 120 mg - 160 mg)
Pharmacist and nurse coordinate with
patient to establish next dosing level
Counseling provided by all team
members, with nurses and pharmacists
leading discussion of anticipated toxicity

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36. Management of AEs Associated With Regorafenib!

AE Before Starting Treatment
Examination of the hands
Gales Supportive measures as indicated

HFSR ee Derene! Regorafenib interruption and dose adjustment in line with prescribing

Advise patients to avoid Information

friction or stress on skin
+ Monitor blood pressure at least weekly
+ Advise patients to measure and record BP at home and to report
elevation above a specified level

+ Pre-existing hypertension + Hypertension control with appropriate antihypertensive therapy, such as
Hypertension should be controlled before ACE inhibitors with sequential addition of a B-blocker and calcium
‘treatment initiation antagonist, if needed

+ Avoid diuretics
+ Regorafenib interruption and dose adjustment in line with
prescribing information

+ Gentle exercise may be helpful
+ Thyroid replacement if hypothyroidism occurs
Fatigue + Prophylactic oral dexamethasone has been reported to lessen fatigue
+ Regorafenib interruption and dose adjustment, in line with prescribing
information, may be needed for persistent fatigue
4. Loupakis Fel al. Thr Adv Med Oncol 2020,121-2. PeerView

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37. tment initiated at

80 mg QD
Mitchell, a 62-year-old man presenting with 120 mg QD
mCRC
At initial presentation, ECOG PS 1 160 mg QD
KRAS mutated (non-G12C)
First line: FOLFOX + bevacizumab ReDOS strategy was appropriate for this
h de patient. However, let's assume the patient
ne auiened to capaniebine presents with grade 2 HFSR. How can the

team manage this event?

Second line: FOLFIRI + bevacizumab

6 = Y” Stop regorafenib; treat with steroid cream
The patient is initiated on third-line TKI

(regorafenib) Y Skip week 3 dose; restart at 120 mg
once toxicity resolves

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38. + Pre-emptive clobetasol might
lessen regorafenib-induced
HFSR compared with
reactive therapy!

Application of clobetasol
0.05% cream to the palms
and soles twice per day for 8
weeks in patients receiving
regorafenib (N = 55)

1. ai et a, Oncologist, 2021;28:610-618,

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How Else Can We Mitigate HFSR

Over the first two cycles

No evidence of HFSR in 30% of patients treated
with pre-emptive clobetasol vs 13% with reactive
clobetasol (P = .03)

During cycle 1
54% and 45% of patients had no HFSR with
pre-emptive and reactive clobetasol, respectively

During cycle 2
33% and 15% had no HFSR with pre-emptive
and reactive clobetasol, respectively (P = .02)

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39. With TAS-102, Prepare for Neu
and Anemia!

penia, Leukopenia,

TAS-102 (n = 533) Placebo (n = 265)

Adverse Event, %
Any Grade Grade >: Any Grade Grade 23
Nausea 48 2 24 1
Vomiting 28 2 14 <1
Decreased appetite 39 4 29 5
Fatigue 35 4 23 6
Diarrhea 32 3 12 <1
Abdominal pain 21 2 18 4
Fever 19 1 14 <1
Asthenia 18 3 "1 E
Laboratory Abnormalities, %
Neutropenia 67 38 <1 o
Leukopenia 77 21 5 o
Anemia 77 18 33 3
Thrombocytopenia 42 5 8 <1
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1. Mayer RJ et al. N Eng! J Med, 2015:372:1909-1910.

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40. How Would the Team Address AE Management

TAS-102 With or Without Bevacizumab

Dose Reductions to Manage AEs |

+ TAS-102 + bevacizumab
+ TAS-102 35 mg/m? up to a
maximum dose of 80 mg

per dose (based on the
trifluridine component)

+ PO twice daily on days 1-5
and 8-12

« Bevacizumab 5 mg/kg on
days 1 and 15

+ Repeat every 28 days

Maximum of 3 dose
reductions permitted to
20 mg/m? per day

Do not escalate dose
after reduction

If AE present at start of cycle — delay treatment
If AE present during the cycle — withhold treatment

For grades 3 or 4

nonhematologic AEs, Resume treatment

ata dose that is
5 mg/m? lower
than previous dose

delay/hold treatment
until AEs resolves to
grades 0-1

Note: Biweekly administration
(days 1-5 and 15-19 of every
28-day cycle) may be easier to
tolerate for patients2.3

1.NCCN Chic Practice Gukeknes in Oncology. Colon Cancer. Version 42025. pn ne orbrfesionaliohyaian „edel. io
2 Yoshida Y ll. Andconcor Ros. 2016,38.4307.4373 2. Yoshida Y et J Anus Rectum Colon, 2019.2.136-141 PeerView

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41. e-Homes for Tea Later Lines of Therapy With mCRC

dé à

| Effective therapy is available for later-line management of mCRC |

+ Agents such as regorafenib, fruquintinib, and TAS-102 + bevacizumab
are among the validated options for later-line CRC management

+ Patient choice, tolerability, and QOL are important factors to consider
when developing treatment goals for later-line care

+ Oncologists, nurses, and other team members should be aware of the
evidence-based dosing strategies for these agents, which can aid in
delivering effective care, helping patients stay on treatment, and

\ mitigating toxicity |
N 4

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