describes the aims of treatment of metastatic colon cancer in view of the recently introduced agents specific for third line treatment

1. Metastatic Colorectal Cancer:
A New Chapter in The Story
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
10th Annual international conference of
clinical oncology department, Assiut university
Servier Symposium
Luxor 20-22/02/2019

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
Speaker Disclosures:

4. Increased Number of Treatment Lines Is
Associated With Survival Benefit in mCRC
*P<.001
SEER Medicare Database Analysis for mCRC (2003 to 2007; N = 5129)
SEER, Surveillance, Epidemiology, and End Results Program
Hanna N, et al. J Clin Oncol. 2014;32(Suppl 3): Abstract 559.
MedianOS,
Months
11.9
23.2
26.4
6.8

5. Typical Survival Pattern in mCRC
47%
13%
10%
10%
10%
10%
Survival (months)
1st Line 2nd Line Break 3rd Line Rechallenge Pre-Terminal
Courtesy: Eric Van CutsemGrothy A. JNCCN. Volume 13 Number 5.5 May 2015
5-7 months
4 - 6 months

6. 1st Line 2nd Line 3rd Line

7. 34 RCTs
13787 Patients

8. Evidence Based Data for 2nd L:
Treatment Arms HR OAS HR PFS
Irinotecan > BSC 0.58 --
Modern Cth. FOLFOX/FOLFIRI > 5-Fu 0.69 0.59
Irinotecan Combinations > Irinotecan -- 0.68
Targeted Agents + Cth > Cth 0.84 --
Bevacizumab -- 0.67
Tumor Response in Parallel with Survival
Mocellin et al. Second-line systemic therapy for metastatic colorectal cancer.
Cochrane Database of Systematic Reviews 2017, Issue 1
www.cochranelibrary.com Accessed 15/09/2018
Disease Stability Beyond 1st Line

9. Therapeutic Goal? Be Realistic:
FDA & EMA APPROAVALS:
• Relative Improvement of mOAS (20%, 2.5 – 6 months) from median Baseline.
• PFS and ORR.
Tanios Saab. Expert Rev. Pharmacoecon. Outcomes Res. 15(1), (2015)

10. Therapeutic Goal? Be Realistic:
5751 Patients

11. Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60
Treatment Goals
“Maintain QoL Across Treatment Journey”
1st Line
OAS ORR Shrinkage
2nd & 3rd Subsequent
Therapies
PFS
Different Goals Across Treatment
Lines:

12. 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

13. mCRC: Chemotherapy as 3rd Line Therapy

14. 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

15. CRYSTAL
5
COI
N3
PRIM
E4
NORDIC
VII2
CO.1
79
40
88
N014
71
PFS for EGFR inhibitors improves across lines of
therapy in KRAS wild-type patients:
Hazard
ratio
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
Study
1817
EPIC
6
Albert Sobrero , WCGIC 2012

16. 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

17. 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.
• Usually monotherapies are preferred.
Lee et al. JCO. 2014;32.12(April 20).

18. 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

19. 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

20. 6.4 vs 5 ms
HR = 0.77
1.9 vs 1.7 ms
HR = 0.49
HR = 0.31
HR = 0.55
Regorafinib in CORRECT & CONCUR:
Grothy et al. Lancet 2013; 381: 303–12 JinLi et al. Lancet Oncol 2015; 16: 619–29

21. Regorafinib in CORRECT & CONCUR:
Grothy et al. Lancet 2013; 381: 303–12

27. 5-FU activity in CRC:
Thymidylate Synthase TS DNA Synthesis & Repair
5-Fu


Amplification
5-Fu
Resistance
TS
Stable
++ Cell Kill
Jason et al. Gene Expr. 2007;13:227-39.
DPD
Degradation
Toxicity
TERMINAL HALF LIFE TIME = 8 – 20 minutes
 Rapid Washout from Circulation
(Hepatic Catabolism)

28. TAS – 102 Activity:
 TS
++ Potent
++ Bioavailability
Than 5-FU
Chen et al. ANTICANCER RESEARCH 36: 21-26 (2016)
Tanaka et al .Oncol Rep 32(6): 2319-2326, 2014.

29. TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL)
800 Patients
Refractory mCRC
2:1 Randomization
1ry End Point: OAS
2nd End Point: PFS & Safety
Placebo + BSC
N=266
Trifluridine - Tipiracil
N=534
1. Mayer RJ et al. N Engl J Med. 2015;372:1909-1919. 2. European Medicines Agency. CHMP
assessment report: Lonsurf – INN: trifluridine/tipiracil (February 25, 2016). BSC: best supportive care.
OS: overall survival. PFS: progression-free survival.
Treatment continuation until progression, intolerable toxicity, or patient
refusal
Sites2: 13 countries in Europe (55), Australia (5), Japan (20) and United
States (21); 101 sites

30. TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL): OAS
7.2 m
5.2 m
HR: hazard ratio. *Both arms received best supportive care.
1. Mayer RJ et al. N Engl J Med. 2015;372 (20) . 2. Van Cutsem E et al. Eur J Cancer. 2017;90:63-72
31%  Risk of Death

31. 26.6% of patients treated with LONSURF were still alive at 1 year vs 17.6% with placebo (primary OS analysis)*
HR: hazard ratio. *Both arms received best supportive care.
1. European Medicines Agency. CHMP assessment report: LONSURF® – INN: trifluridine/tipiracil (February 25, 2016).
27%
of patients treated with
LONSURF were still
alive at 1 year
vs 17% with placebo
(Confirmation of the statistically
significant 1 year survival rate in
the updated OS analysis)
TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL)

32. TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL): PFS
47.2%
20.8%
52%  Progression

33. 44% of patients treated with LONSURF had their disease controlled vs 16% with placebo*
CR: complete response PR: partial response
1. Mayer RJ et al. N Engl J Med. 2015;372 (20)
TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL): DC
The overall response rate was 1.6%
with LONSURF vs 0.4% with placebo
(P=0.29; CR, 0% with LONSURF vs
0.4% with placebo; PR, 1.6% with
LONSURF vs 0% with placebo).

34. TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL): PS > 2
*Both arms received best supportive care. 1. Mayer RJ et al. N Engl J Med. 2015;372 (20)

35. LONSURF preserves performance status1
1. Van Cutsem E et al. Eur J Cancer. 2017;90:63-72. 2. Oken MM, et al. Am J Clin Oncol. 1982;5(6):649-655. 3. Van Cutsem E, et al. ESMO Open. 2017;2(5):e00261
Changes in ECOG performance status from baseline to treatment discontinuation
in LONSURF group2
84%
of patients treated with LONSURF
were still at
PS 0-1 at treatment
discontinuation3
mCRC patients treated
with LONSURF are able
to receive subsequent
therapies
TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL)

36. TAS 102 in Refractory Metastatic CRC:
(RECOURSE TRIAL): Adverse Events
G3 AEs
> 1 week
1 week Rest
 5 mg/m2
3 Events
Withdrawal
1. Mayer RJ et al. N Engl J Med. 2015;372 (20):1909-19

37. 7.8 m
7.1 m
2.0 m
1.8 m

40. Take Home Message:
• Therapeutic Platform of mCRC has been expanded over
the past few years; med OAS around 30 months.
• QoL should be ensured across all therapy lines.
• PFS and DC as a surrogate for OAS.
• TAS 102 & Regorafinib are key-players 3rd L mCRC
• TAS 102 versus Regorafinib:
– Comparable OAS & PFS.
– TAS 102 better QoL, compliance & toxicity profiles

41. Thank You.