Optimizing Sequencing for Colorectal Cancer ‐ What is Best and When? Bassel F. El ‐ Rayes, MD Associate Professor of Medical Oncology Associate Director for Clinical Research and Director of GI Oncology Program Winship Cancer Institute Emory University Disclosures • Research support: Bayer, Genentech ‐ Roche 1
Stage IV CRC: 2014 1980 1985 1990 1995 2000 2005 2010 Best supportive care 5-FU Irinotecan 30 Capecitabine Oxaliplatin Cetuximab 20 OS (Mos) Bevacizumab Panitumumab 10 Ziv-aflibercept Regorafenib Median OS 0 1980 1985 1990 1995 2000 2005 2010 Yr Primary Management (Frontline) of Colorectal Cancer 2
Colorectal Cancer Stage IV Colorectal Cancer Clinical Presentation Mutational Status Resectable : Y Borderline No Ras : Mutant No Survival After Primary or Secondary Resection of Liver Metastases Resectable (n = 425) Initially non resectable (n = 95) 54% 34% 27% 50% 34% 29% 0 1 2 4 8 3 5 6 7 9 10 Survival Time (years) Bismuth et al, 1996 3
EORTC: Resectable Liver Metastases 100 80 HR: 0.77 (95.66% CI: 0.60-1.00; P = .041) 60 +8.1% at 3 yrs PFS (%) 36.2% 40 Periop CT 28.1% 20 Surgery only 0 0 1 2 3 4 5 6 Yrs • 5 ‐ yr OS rate was not significantly different between FOLFOX or surgery alone (51.2% vs 47.8%; P = .34) Nordlinger B, et al. Lancet. 2008;371:1007-1016. Nordlinger B, et al. Lancet Oncol. 2013;14:1208-1215. FOLFOX / FOLFIRI Tournigand, C. et al. J Clin Oncol; 22:229-237 2004 Colucci, G. et al. J Clin Oncol; 23:4866-4875 2005 4
Key First ‐ line Chemotherapy Trials in mCRC: Efficacy Comparative Regimens Median PFS, Mos Median OS, Mos IFL vs FOLFOX vs IROX [1] 6.9 vs 8.7 vs 6.5 15.0 vs 19.5 vs 17.4 FOLFIRI vs FOLFOX4 [2] 7.0 vs 7.0 14.0 vs 15.0 XELOX (CapeOx) vs FOLFOX4 [3,4] 7.3 vs 7.7 19.0 vs 18.9 FOLFIRI vs mIFL vs CapeIRI [5] 7.6 vs 5.9 vs 5.8 23.1 vs 17.6 vs 18.9 1. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866-4875. 3. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012. 4. Cassidy J, et al. Br J Cancer. 2011;105:58-64. 5. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786. AVEX: PFS The Lancet Oncology null 2013 null http://dx.doi.org/10.1016/S1470 ‐ 2045(13)70154 ‐ 2 5
FOLFOXIRI as First ‐ line Therapy Trial RR, % Median TTP/PFS, Mos Median OS, Mos Souglakos 43.0 vs 33.6 8.4 vs 6.9 21.5 vs 19.5 (n = 283) Falcone 60 vs 34* 9.8 vs 6.9* 22.6 vs 16.7* (n = 244) *Statistically significant difference. Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676. Ongoing Trial FOLFOX +Bev CRC Stage IV m ‐ FOLFIRINOX +Bev Previously untreated FOLFIRINOX+ Bev 6
Targeting VEGF Phase III Trial of Bevacizumab + IFL Second-line Placebo + IFL PD chemotherapy, (n=411) no Bev Previously Bevacizumab Second-line untreated mCRC (5 mg/kg, q2w) PD chemotherapy N=923 + IFL (n=402) ± Bev Bevacizumab Second-line PD (5 mg/kg, q2w) chemotherapy + 5-FU/LV (n=110) ± Bev • Primary endpoint: overall survival • Secondary endpoints: PFS, RR, safety, response duration * PD = progressive disease. Hurwitz et al. N Engl J Med . 2004;350:2335. 7
Overall Survival 100 Median survival Placebo + IFL: 15.6 months Bev + IFL: 20.3 months 80 HR=0.66, P <0.001 Placebo + IFL (n=411) 60 Bev + IFL (n=402) OS (%) 1-year survival 40 74% vs 63% 20 2-year survival 45% vs 30% 0 0 6 12 18 24 30 Months Error bars represent 95% CIs. Hurwitz et al. N Engl J Med . 2004;350:2335. Bev/Irinotecan ‐ Based Regimens Trial AVF2107 BICC-C PACE (N=411 vs 402) (N=57 vs 60) (N=115) Treatment IFL +/ ‐ Bev Bev+ IFL or FOLFIRI Iri/Bev 15.6 vs 20.3 28.0 vs 19.2 20.5 OS <0.001 0.037 6.2 vs 10.6 11.2 vs 8.3 11.7 PFS <0.001 0.28 34.8 vs 44.8 57.9 vs 53.3 40% RR 1.Hurwitz, H N Engl J Med . 2004;350:2335. 2. Fuchs , CJ CO2007 3. Hect, JR JCO 2009 8
Bev/Oxaliplatin ‐ Based Regimens Trial NO16966 PACE CARIO 2 (N=701 vs 699) (410) (N=375) Treatment FOLFOX/XELOX +/ ‐ FOLFOX+ Bev XELOX/Bev Bev 19.9 vs 21.2 24.5 20.4 OS 0.077 8.0 vs 9.4 11.4 10.7 PFS 0.0023 On-treatment : 7.9 vs 10.4 <0.0001 38 vs 38 48 40 RR 1.Cassidy, J JCO 2008 2. Hecht, JR JCO 2009 3. Tol, J New Eng JM 2009 Targeting EGFR 9
The Ras Mutation Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007 Retrospective Studies: KRAS Interaction With EGFR Inhibitors RR N (% Study Regimen Mutan mKRAS) WT t Lievre, 2008 Cetuximab 114 (32) 44 0 De Roock, 2008 CT + Cetuximab 113 (41) 41 0 Tejpar, 2008 Irinotecan + Cetuximab 89 (36%) 37 0 Tabernero, 2008 Cetuximab 48 (41) 28 0 Di Fiore, 2007 CT + Cetuximab 59 (37) 12 0 Finocchiaro, 2007 Cetuximab ± CT 81 (40) 27 6 Khambata-Ford, Cetuximab 80 (38) 10 0 2007 Amado, 2008 Panitumumab 208 (40) 17 0 Lievre. J Clin Oncol. 2008;26:374; De Roock. Ann Oncol. 2008;19:508; Tejpar. ASCO. 2008 (abstr 4001); Tabernero. ASCO GI. 2008 (abstr 435); Di Fiore. Br J Cancer. 2007;96:1166; Finocchiaro. ASCO. 2007 (abstr 4021); Khambata-Ford. J Clin Oncol. 2007;25:3230; Amado. J Clin Oncol. 2008;26:1626. 10
First Line EGFR ‐ Targeted Agents Trial Comparative Regimens Median PFS, Mos Median OS, Mos CRYSTAL [1] FOLFIRI/Cetux vs FOLFIRI 9.9 vs 8.4 23.5 vs 20.0 FOLFOX4/Pmab vs FOLFOX4 9.6 vs 8.0 23.8 vs 19.4 PRIME [2 ‐ 4] FOLFOX4/Pmab vs FOLFOX4 10.1 vs 7.9 26.0 vs 20.2 (KRAS/NRAS WT) FOLFOX/XELOX/Cetux vs COIN [5] 8.6 vs 8.6 17.0 vs 17.9 FOLFOX/XELOX • Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease [3] 1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Douillard JY, et al. J Clin Oncol. 2010;28:4697- 4705. 3. Douillard JY, et al. ASCO 2013. Abstract 3620. 4. Douillard JY, et al. N Engl J Med. 2013;369:1023- 1034. 5. Maughan TS, et al. Lancet. 2011;377:2103-2114. Are all KRAS mutations the same? 11
Analysis of KRAS/NRAS Mutations PFS Subgroup n HR for Progression or Death (95% CI) Primary analysis Nonmutated KRAS exon 2 656 0.80 (0.66 ‐ 0.97) Mutated KRAS exon 2 440 1.29 (1.04 ‐ 1.62) Prospective ‐ retrospective analysis Nonmutated RAS 512 0.72 (0.58 ‐ 0.90) Mutated RAS 548 1.31 (1.07 ‐ 1.60) Nonmutated KRAS exon 2, mutated other RAS 108 1.28 (0.79 ‐ 2.07) 0.40 0.63 1.00 1.58 2.51 Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better OS Subgroup n HR for Progression or Death (95% CI) Primary analysis Nonmutated KRAS exon 2 656 0.83 (0.67 ‐ 1.02) Mutated KRAS exon 2 440 1.24 (0.98 ‐ 1.57) Prospective ‐ retrospective analysis Nonmutated RAS 512 0.78 (0.62 ‐ 0.99) Mutated RAS 548 1.25 (1.02 ‐ 1.55) Nonmutated KRAS exon 2, mutated other RAS 108 1.29 (0.79 ‐ 2.10) 0.40 0.63 1.00 1.58 2.51 Panitumumab-FOLFOX4 Better FOLFOX4 Alone Better Douillard JY, et al. N Engl J Med. 2013;369:1023-1034. BRAF Mutation Status KRAS WT/ BRAF WT KRAS WT/ BRAF MT (n = 566) (n = 59) CRYSTAL Trial FOLFIRI Cetuximab + FOLFIRI Cetuximab + FOLFIRI FOLFIRI (n = 289) (n = 277) (n = 33) (n = 26) Median OS, mos 21.6 25.1 10.3 14.1 (95% CI) (20.0-24.9) (22.5-28.7) (8.4-14.9) (8.5-18.5) HR (95% CI) 0.830 (0.687-1.004) 0.908 (0.507-1.624) Median OS: 23 Median OS: 23 Median OS: Median OS: P value* .0547 .7440 mos mos 12 mos 12 mos Median PFS, mos 8.8 10.9 5.6 8.0 (95% CI) (7.6-9.4) (9.4-11.8) (3.5-8.1) (3.6-9.1) HR (95% CI) 0.673 (0.528-0.858) 0.934 (0.425-2.056) P value* .0013 0.8656 OR rate, % 42.6 61.0 15.2 19.2 (95% CI) (36.8-48.5) (55.0-66.8) (5.1-31.9) (6.6-39.4) P value † < .0001 .9136 *Stratified log-rank test. † Cochran-Mantel-Haenszel test. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011 ‐ 2019. 12
KRAS status does not impact antiangiogenic therapy outcome No Impact for KRAS status 13
Bevacizumab Shows PFS Benefit Regardless of KRAS Status Mutant KRAS Wild ‐ Type KRAS (n=78) (n=152) Median PFS Median PFS 1.0 1.0 IFL + Placebo 5.5 mo IFL + Placebo 7.4 mo IFL + Bev 9.3 mo IFL + Bev 13.5 mo 0.8 0.8 Proportion Progression Free Proportion Progression Free HR=0.41; P =0.0008 HR=0.44; P <0.0001 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 5 10 15 20 25 0 5 10 15 20 25 Duration of PFS (Months) Duration of PFS (Months) Rosen. Ann Oncol. 2008;19:vi19 (abstr O ‐ 035). VEGFI or EGFRI in Frontline Setting? 14
FIRE ‐ 3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT FOLFIRI + Cetuximab FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 IV 120 min initial dose Cetuximab: 400 mg/m 2 IV 120 min initial dose 250 mg/m 2 IV 60 min q1w 250 mg/m 2 IV 60 min q1w mCRC first ‐ line mCRC first ‐ line Randomize therapy therapy 1:1 KRAS wild ‐ type KRAS wild ‐ type FOLFIRI + Bevacizumab FOLFIRI + Bevacizumab (N = 592) (N = 592) Bevacizumab: 5 mg/kg IV 30 ‐ 90 min q2w Bevacizumab: 5 mg/kg IV 30 ‐ 90 min q2w • Primary endpoint: ORR (mRECIST 1.0) • Amendment in October 2008 to include only KRAS WT (ex 12/13) pts • 150 active centers in Germany and Austria Heinemann V, et al. ASCO 2013. Abstract LBA3506. FIRE ‐ 3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT 28.7 1.00 mos Cetuximab + CT (FOLFIRI) Bevacizumab + CT (FOLFIRI) 0.75 OS Estimate ∆ = 3.7 mos 0.50 25.0 mos 0.25 HR: 0.77 P = .017 0 0 12 24 36 48 60 72 Mos Since Start of Treatment Cetuximab + CT Bevacizumab + CT P Value ORR, % 62 58 .183 (primary endpoint not met) PFS, mos 10.0 10.3 .547 Heinemann V, et al. ASCO 2013. Abstract LBA3506. 15
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