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Optimal Systemic Treatment Strategy for Advanced RAS Mutant Colorectal Cancer

This presentation discusses the importance of RAS testing and the selection of an optimal treatment strategy for advanced RAS mutant colorectal cancer. It covers topics such as the relevance of tumor sidedness, outcome after regional management, and subsequent lines of therapy.

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Optimal Systemic Treatment Strategy for Advanced RAS Mutant Colorectal Cancer

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  1. 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 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. Treatment of mCRC in 2016Individualisedtreatmentconcept in metastatic CRC Assessment of clinical condition of the patient Fit Unfitbut maybe suitable Unfita BSC FP + bevacizumab; reduced dose doublet; anti-EGFR Goal Patients with clearly resectable metastases Cytoreduction (Tumor Shrinkage) Disease control (Control of progression) Molecular profile Molecular profile Surgery alone with perioperative postoperative CT BRAFmt RAS wt RASmt RAS wt RASmt BRAFmt 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 *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 ClinOncol 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 ClinOncoI 2010;28:4706–4713; 7. Giantonio BJ, et al. J ClinOncol 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 ClinOncol 2008;26:1626–1634

  7. RAS Mutation: Prognostic vs Predictive

  8. RAS Mutation: Prognostic vs Predictive

  9. RAS Mutant mCRC

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

  11. 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 NB: statistically significant results are highlighted in blue 1. Saltz, et al. JCO 2008; 2. Hurwitz, et al. NEJM 2004 3. 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 HR 0.58 OS HR 0.69 Hurwitz et al., The Oncologist 2009

  18. Bevacizumab in RAS Mutant Disease

  19. Maintenance Therapy in RAS Mutant mCRCAIO 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. O 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):760-768

  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)

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