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

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 ?????

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

Importance of RAS Testing in mCRC

(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

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

RAS Mutation: Prognostic vs Predictive

RAS Mutation: Prognostic vs Predictive

RAS Mutant mCRC

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

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

Selection of First Line Chemotherapy in Ras Mutant mCRC

Doublet vs Triplet

RAS Mutation and Triplet

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

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 2004 3. Kabbinavar, et al. JCO 2005; 4. Tebbutt, et al. JCO 2010

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

Bevacizumab in RAS Mutant Disease

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

TML Study: RAS Mutant Population

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

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

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

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

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)