1. Ali Shamseddine,MD,FRCP
Optimal Systemic Treatment Strategy for Advanced RAS Mutant Colorectal Cancer
Ali Shamseddine,MD,FRCP
Professor of Clinical Medicine
American University of Beirut Medical Center
8th IGCC Dec. 7-9, Istanbul - Turkey

2. Colon Cancer: More Than 1 Disease
Molecular
MSI,Her-2/neu & BRAF
RAS WT vs MUT
Anatomic
MSI, microsatellite instable; MSS, microsatellite stable; MUT, mutated; WT, wild type.
Right vs Left
Rectal vs Colon
Stool Flora Types
?????

3. Management of RAS Mutant mCRC
Importance of initial RAS testing ( prognostic vs predictive)
Selection of an optimal 1st-line chemotherapy in RAS mutant mCRC
First-line targeted therapy in RAS mutant mCRC
Relevance of tumor sidedness in RAS mutant tumors
Outcome after regional management in RAS mutant CLM
Subsequent lines with TKI‘s in RAS mutant mCRC

4. Importance of RAS Testing in mCRC

5. (Control of progression)
Treatment of mCRC in 2016 Individualised treatment concept in metastatic CRC
Assessment of clinical condition of the patient
Fit
Unfit but maybe suitable
Unfita
FP + bevacizumab; reduced dose doublet; anti-EGFR
BSC
Goal
Patients with clearly resectable metastases
Cytoreduction
(Tumor Shrinkage)
Disease control
(Control of progression)
Molecular profile
Molecular profile
Surgery alone with perioperative postoperative CT
RAS wt
RAS mt
BRAF mt
RAS wt
RAS mt
BRAF mt
CT doublet
+ anti EGFR
Combination CT
+ bevacizumab
CT triplet
+ bevacizumab
CT doublet
+ biological agent
CT doublet
+ bevacizumab
CT triplet
± bevacizumab
Van Cutsem E, et al. Ann Oncol 2016

6. Greatest Treatment Efficacy in 1st-Line
Parameter*
1st line
2nd line
Later lines
Response rate
38–64%1,2
10–35%5,6
1–13%8,9
Progression-free survival
8–11 months3,4
4–7 months5,7
2–3 months8,10
*Range of results for targeted treatment arms of key Phase II and III trials (KRAS wt exon 2 for EGFR inhibitor trials)
Conclusion: 1st line therapy is a critical determinant of overall survival
1. Maughan TS, et al. Lancet 2011;377:2103–2114; 2. Saltz LB, et al. J Clin Oncol 2008;26:2013–2019; 3. Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546; 4. Hurwitz H, et al. New Engl J Med 2004;350:2335–2342; 5. Langer C, et al. ESMO 2008 (Abstract No. 385P); 6. Peeters M, et al. J Clin OncoI 2010;28:4706–4713; 7. Giantonio BJ, et al. J Clin Oncol 2007;25:1539‒1544; 8. Grothey A, et al. Lancet 2013;38:303–312; 9. Karapetis CS, et al. N Engl J Med 2008;359:1757‒1765; 10. Amado RG, et al. J Clin Oncol 2008;26:1626–1634

7. RAS Mutation: Prognostic vs Predictive

8. RAS Mutation: Prognostic vs Predictive

9. RAS Mutant mCRC

10. Presented By Ryan Corcoran at 2018 ASCO Annual Meeting
KRAS vs NRAS
Slide 14
Presented By Ryan Corcoran at 2018 ASCO Annual Meeting

11. Presented By Ryan Corcoran at 2018 ASCO Annual Meeting
KRAS vs NRAS
Conclusions
Presented By Ryan Corcoran at 2018 ASCO Annual Meeting

12. Selection of First Line Chemotherapy in Ras Mutant mCRC

13. Doublet vs Triplet

14. RAS Mutation and Triplet

15. First-line Targeted Therapy in mCRC (RAS mut & BRAF WT)

16. Efficacy of bevacizumab in randomized phase III trials in 1° line metastatic CRC
Treatment regimen n
Median PFS (months)
Median OS (months)
RR (%)
FOLFOX/CAPOX ± bevacizumab1
1,400
9.4 vs 8 HR=0.83
21.3 vs 19.8 HR=0.89
38 vs 38
IFL ± bevacizumab2
813
10.6 vs 6.2 HR=0.54
20.3 vs 15.6 HR=0.66
45 vs 35
5-FU/LV ± bevacizumab3 (pooled analysis)
241
8.8 vs 5.6 HR=0.63
17.9 vs 14.6 HR=0.74
34 vs 24
Capecitabine ± bevacizumab4
313
8.7 vs 5.7 HR=0.63
18.9 vs 18.9 HR=0.88
56 vs 43
NB: statistically significant results are highlighted in blue
1. Saltz, et al. JCO 2008; 2. Hurwitz, et al. NEJM Kabbinavar, et al. JCO 2005; 4. Tebbutt, et al. JCO 2010

17. IFL +/- Bevacizumab phase III trial KRAS analysis subgroup (N=230)
PFS
HR 0.44
HR 0.41 OS
HR 0.58
HR 0.69
Hurwitz et al., The Oncologist 2009

18. Bevacizumab in RAS Mutant Disease

19. Maintenance Therapy in RAS Mutant mCRC AIO 0207 Study, non-inferiority, 472 pts

20. TML Study: RAS Mutant Population

21. Is Primary Tumor Location a Prognostic feature in RAS Mutant mCRC?
Loupakis F. The Oncologist 2018; 23:1-3

22. Outcome Following RFA in RAS Mutant CLM
92 pts, 36 (39%) RAS mutant
LTP-free survival 35% vs 71%
p=0.001
Odisio CB. Br J Surg 2017:104(6):

23. Single Agent Regorafenib after Failure of First-line Therapy with FOLFOXIRI plus Bevacizumab in any RAS or BRAF Metastatic Colorectal Cancer
Single arm Phase II study with planning to recruit 53 pts to achieve a 30% PFS at 6M
Results: No patient was progression-free at 6 month
Median PFS: 2.2M, TTP: 2M and OS: 3.3M
Gracia-Alfonso P. The Oncologist 2018;23:1271

24. Conclusions (1)
-RAS Testing is mandatory in patients with mCRC -First-line therapy is a critical determinant of overall survival -Triplet is not better than doublet in RAS mutant mCRC -NRAS mutations carry a poorer prognosis compared to KRAS mutations -Targeted therapy with Bevacizumab may be considered with doublet as 1st line therapy in RAS mutant mCRC but the evidence is still insufficient -No survival advantage when Bevacizumab is continued beyond progression in mutant mCRC

25. Conclusions (2)
-In RAS mutant disease maintenance therapy with 5-FU plus Bevacizumab is superior to single agent -Tumor sidedness is not a prognostic feature in RAS mutant mCRC (No difference in OS) -Mutant RAS tumors are associated with an earlier and higher rate of local tumor progression in patients undergoing ablation of CLM -Regorafenib failed to demonstrate clinical activity in RAS or BRAF- mutated mCRC following first line failure with FOLFOXIRI plus Bevacizumab (Needs to be confirmed in a larger study)