Describes the different therapeutic approach to patients with metastatic colorectal cancer in the 3rd subsequent treatment line with especial emphasis on the role of regorafenib and how to manipulate the adverse events while not compromise the outcome.

1. Expanding Treatment Platform
in mCRC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Bayer Symposium
Asyut University Annual Cancer Conference
Wednesday, 21/02/2018

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly, Bayer
Speaker Disclosures:

3. mCRC:
The Expanding Landscape
mOAS
> 30 months
Efficacy of 1st L
“Biomarker”
Resection/Ablation of
Organ Limited Disease
More Subsequent
Treatment Options
Treatment Holidays (QoL)
Maintenance Therapy
Re-challenge Beyond
Progression
Treatment Intensification
MDT Approach
1ry Tumor Location
Tumor Immunogenicity
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

4. First Line Options
Combination
Therapy
Second Line Options
Combination
Therapy
Third Line Options
Good PS & Sypmt.
 Monotherapy or
Re-challenge
Poor PS or Asympt.
 BSC
Beyond combination therapy in first and
second line – A heterogeneous situation
(5-Fu/Leucovorin or Cape) +/- Oxaliplatin
+/- Irinotecan +/- Anti-EGFR or VEGF/R
Chemo or Anti-EGFR
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

5. Survival Advantage is Modest
in 2nd & 3 Lines
Parameter 1st Line 2nd Line 3rd Line
OOR (%) 38 - 69 10 - 41 1 - 22
PFS (ms) 9 - 13 4 - 9 2 - 4
mCRC:
“Different Goals on Subsequent Treatments”
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60
Treatment Goals
“Maintain QoL Across Treatment Journey”
1st & 2nd
Subsequent Therapies
OAS ORR Shrinkage
3rd Line
PFS

6. 1st Line 2nd Line 3rd Line

8. mCRC: Chemotherapy as 3rd Line Therapy

9. mCRC: Chemotherapy as 3rd Line Therapy
49 Chemorefractory
(PS 0 – 1)
CR =
2%
PR =
16%
SD =
45%
PD =
37%
mOAS = 11.9 months
mPFS = 5.8 months

10. CRYSTAL5
COIN3
PRIME4
NORDICVII2
CO.179
4088
N01471
PFS for EGFR inhibitors improves across lines of
therapy in KRAS wild-type patients:
Hazardratio
1. Alberts, et al. JAMA 2012;2OCJ .la te ,tievT .2012;3tecnaL .la te ,nahguaM .2011
4. Douillard, et al. ASCO 2011;5OCJ .la te ,mestuC naV .2011;6OMSE .la te ,regnaL .2008
7. Sobrero, et al. ASCO GI 2012;8OCJ .la te ,odamA .2008;9MJEN .la te ,stieparaK .2008
First line Second line Salvage
(single agent)
Adjuvant
1.2
1.0
0.8
0.6
0.4
0.2
0
Study1817
EPIC6
Albert Sobrero , WCGIC 2012

11. mCRC: EGFR Inhibitors as a 3rd Line
Karapetis et al.N Engl J Med 2008;359:1757-65.
Kim et al. bjc.2016.309.
Price et al. Lancet Oncol 2014; 15: 569–79
CETUXIMAB PANITUMUMAB ASPECCT TRIAL

12. The Ideal Therapy in 3rd L
• Quality of Life should be maintained.
• PFS & disease stabilization is the main goal.
• Current reported baseline mOAS 4 – 6 months.
• Clinically meaningful improvement of survival
would be 3-5 months.
• The preferred HR is < 0.67
• Usually monotherapies are preferred.
Lee et al. JCO. 2014;32.12(April 20).

13. Factors Affecting Treatment Selection
in 3L of mCRC:
• Patient-related factors (e.g. comorbidities) as
well as patient preferences and motivation,
which becomes more important in this setting
• Disease-related factors (e.g. molecular
characteristics, tumor- related symptoms,
growth dynamics and manifestation)
• Treatment-related factors (e.g. availability,
toxicity and safety profile)
• Prior treatment toxicity, efficacy and
characteristics (e.g. discontinuation before
progression) of combination chemotherapies
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

14. 3rd Line Treatment Options:
Previous
Treatment
& PS
Irinotecan +
Anti-EGFR
Anti-EGFR
TAS 102
Regorafinib
BSC
Clinical Trial
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

15. 3rd Line Data:
Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

16. Mode of Action of Regorafenib
• Regorafenib inhibits multiplecell-
signaling kinases:
– Angiogenic
• VEGFR1–3, TIE2
– Stromal
• PDGFR-β, FGFR
– Oncogenic
• KIT, PDGFR, RET
• T1/2 in man: approx. 26-28hrs
– Two major metabolites (M2,
M5) are pharmacologically
active
Wilhelm SM et al. Int J Cancer 2011

17. Grothy et al. Lancet 2013; 381: 303–12

18. Regorafinib in mCRC Progressed on
All Standard Therapies:
Grothy et al. Lancet 2013; 381: 303–12
6.4 vs 5 ms
HR = 0.77
1.9 vs 1.7 ms
HR = 0.49

19. Regorafinib: Better Insight

20. Regorafinib: Better Insight
Lung Cavitation
Ricotta R, et al. ESMO Open 2017;1:e000111.
doi:10.1136/esmoopen-2016-000111

21. JinLi et al. Lancet Oncol 2015; 16: 619–29

22. CONCUR Trial in ASIAN Population
JinLi et al. Lancet Oncol 2015; 16: 619–29
HR = 0.31
HR = 0.55

29. SALVAGE Treatment in mCRC:
After failure of fluropyrimidine, oxaliplatin, irinotecan, anti-‐VEGF and anti-‐EGFR (if RASw.t.)
ECOG 0 - 1 ECOG 2
Longest OAS
TAS-102 Regorafenib
Re-
Challenge ?
Re-
Challenge ?
ECOG 3+
Best-
Supportive
Care only
TAS-102

30. Can we improve tolerability?

39. Take Home Message:
• Therapeutic platform of mCRC has expanded.
• Significant proportion of patients will go for
3rd Line upon treatment progression.
• 3rd Line Therapeutic Goals may be different
than 1st and 2nd Lines; QoL & SD.
• Regorafinib is a multikinase inhibitor proved in
randomized phase 3 trials to fulfill the pre-
requisites from 3rd Line treatments while
keeping an eye on AE in relation to OS.