Colon Cancer Molecular Target Agents Ci Caio Max SR S. Rocha Lima, M.D. MD Professor of Medicine CDi CoDiretor Cl Colorectal tlheptobiliary, Pancreatic SDG, and Phase I Unit University of Miami & Silvester Cancer Center
Advances in the Treatment of Colorectal Cancer 2000 2005 2008 2009 2010 5 FU Irinotecan Targeted therapies Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab Ziv Aflibercetp Regorafenib KRAS 5 FU, fluorouracil. National Cancer Institute. Colon cancer treatment (PDQ). 2012. National Cancer Institute. Cancer drug information. 2011.
Advances In Colon Cancer 5-year survival rate for stage IV CRC remains only 6% 2000 Saltz 5-FU/LV bolus 12,6 2000 Douillard 5-FU/LV infusion 14,1 2000 Saltz IFL 14,8 2000 Douillard LVFU2/irinotecan 17,4 2004 Goldberg FOLFOX 19,5 2004 Hurwitz IFL + bevacizumab 20,3 2007 Falcone FOLFOX/FOLFIRI 22,6 2008 2011 2011 Saltz Bokemeyer Van Cutsem XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab 21,3 22.8* 23.5* 2011 Douillard FOLFOX + panitumumab 23.9* 0 5 10 15 20 25 Overall llsurvival l( (months) *KRAS wild type tumors Note: Informal comparison as these are not head to head clinical trials. Saltz. N Engl J Med. 2000. Douilliad. Lancet. 2000. Goldberg. J Clin Oncol. 2004. Hurwitz. N Engl J Med. 2004. Saltz. J Clin Oncol. 2008. Falcone. J Clin Oncol. 2007. Bokemeyer. Ann Oncol. 2011. Van Cutsem. J Clin Oncol. 2011. Douilliard. ASCO; 2011. Abstract 3510.
Targeted Agents Leverage Multiple Pathways Important in CRC Development KRAS Status Is Important for Therapy Selection Endothelial Cell Tumor Cell Targeted dbevacizumab b and aflibercept* Targeted by cetuximab and panitumumab IfKRASin mcrcis mutated, then KRASand downstream pathways are activated even whenegfris inhibited by cetuximab or panitummab that are ineffective. *Aflibercept also targets PIGF Krasinskas AM. Patholog Res Int. 2011;2011:932932. Sitohy B, et al. Cancer Res. 2012;72:1909 1914. Bendardaf R, et al. Anticancer Res. 2008;28:3865 3870. Kitadai Y, et al. Am J Pathol. 2006;169:2054 2065. Jayson GC, et al. J Clin Oncol. 2005;23:973 981.
A Meta analysis Comparing Chemotherapy + Bevacizumab With Chemotherapy Alone in mcrc: HR for PFS and OS HR for PFS Author Study HR (95% CI) Weight, % Year Giantonio E3200 061(051-0 0.61 (0.51 0.73) 22.4 2007 Hurwitz AVF2107 0.66 (0.57-0.75) 24.8 2004 Kabbinavar Phase II 0.45 (0.28-0.72) 8.9 2003 Kabbinavar AVF2192 061(0480 0.61 (0.48-0.78) 18.11 2005 Saltz NO16966 0.83 (0.74-0.94) 25.8 2008 Overall 0.66 (0.56-0.77) 100.0 0.28260 1 1 HR HR for OS 3.53855 Author Study HR (95% CI) Weight, % Year Giantonio E3200 0.75 (0.63-0.89) 28.1 2007 Hurwitz AVF2107 0.66 (0.54-0.80) 0.80) 25.1 2004 Kabbinavar AVF2192 0.79 (0.56-1.11) 13.1 2005 Saltz NO16966 0.89 (0.78-1.02) 33.7 2008 Overall 077(067-0 0.77 (0.67-0.89) 100.00 Cao, et al. Int J Colorectal Dis. 2009;24:677-685. 0.54253 8 1 HR 1.84318 = First line = Second line 5
KRAS Mutations in Colorectal Cancer Growth promoting oncogene activatedby upstream growth factor receptors Mutated in 35 40% of CRC, leads to activation Mutationin in colons 12or 13 (or 61) Not clearly prognostic
Slide 8 Presented By Marc Peeters at 2014 Gastrointestinal Cancers Symposium
PRIME Enrollment target: 1150 patients S C R E E N I N G E N R O L L M E N T Tx Arm 1: Panitumumab 6.0 mg/kg q2w + FOLFOX4 q2w Tx Arm 2: FOLFOX4 q2w Disease assessment every 8 weeks E N D O F T R E A T M E N T L O N G - T E R M F O L L O W - U P Randomization stratification: ECOG score: 0-1 vs 2 Geographic region: Western Europe, Canada, and daustralia vs rest of the world Douillard JY et al. J Clin Douillard Oncol. 2010 J-Y et Oct al. 4 N [Epub Engl J ahead Med 2013;369:1023-1034 of print]. 8
Hazard Ratio for Disease Progression or Death and Hazard Ratio for Death from Any Cause, According to KRAS and RAS Mutation Status. Douillard J-Y et al. N Engl J Med 2013;369:1023-1034
FIRE 3: RESULTS FOLFIRI + FOLFIRI + cetuximab bevacizumab (N = 297) (N = 295) HR (95% CI) ORR 62% 57% PFS 10.3 mos 10.4 mos 1.04 P = 0.69 OS 28.8 mos 25.0 mos 077 0.77 (0.62-0.95) P = 0.016
Probability of survival 1.0 075 0.75 0.50 0.25 FIRE 3: Overall survival RAS* wild type Median Events (months) n/n(%) FOLFIRI + cetuximab 33.1 91/171 (53,2%) FOLFIRI + bevacizumab 25.6 110/171 (64,3%) = 7.5 months HR 0.70 P =0.011 0.0 12 24 36 48 60 72 Months since start of treatment No. at 171 128 71 39 20 6 risk 171 127 68 26 9 1 *KRAS and NRAS exons 2,3 and 4 wt Stintzing S, et al. ECC 2013 (Abstract No. LBA17)
FIRE: updated RAS and RR FOLFIRI + FOLFIRI + cetuximab bevacizumab ORR % 95% CI % 95% CI Odds ratio (95% CI) p-value KRAS wt (exon 2) ITT (N=592) 62.0 56.2 67.5 58.0 52.1 63.7 1.18 (0.85 1.64) 0.183* RAS WT (n=342) 65.5 57.9 72.6 59.6 51.9 67.1 1.28 (0.83 1.99) 0.32** RAS MT (n=65) 38.2 22.2 56.4 58.1 39.1 75.5 0.45 (0.17 1.21) 0.14** KRAS exon 2 and RAS MT (N=178) 38.0 28.1 48.8 51.2 40.1 62.1 0.59 0.32-1.06 0.097** p=*one-sided Fisher s exact test; **two-sided Fisher s exact test Stintzing S, et al. ECCO 2013 (Abstract No. LBA17)
KRAS or RAS : Is this important? Studies Arms mos Kras wt mos RAS wt FIRE FOLFIRI+ Cetuximab FOLFIRI+ Bevacizumab 28,7 25,0 Δ 3,7 33,1 25,6 Δ 7,5 PRIME FOLFOX+ Panitumumab 23,8 Δ 44 4,4 25,8 Δ 56 5,6 FOLFOX 19,4 20,2 PEAK FOLFOX+ Panitumumab 34,2 Δ9,9 41,3 Δ12,4 FOLFOX+ Bevacizumab 24,3 28,9 RAS: KRAS: exon 2 ( codons 12,13),exon 3 (codon61) and exon 4 ( codons 117, 146) NRAS: exon 2 ( codons 12, 13), exon 3 ( codon 61) and exon 4 ( codons 117, 146)
Liver Metastases in Colorectal Cancer: Outcomes Liver Metastases Resectable 20% to 25% Nonresectable 75% to 80% Location Number Size Downsizing Survival Benefit 30% to 40% at 5 years 15% at 10 years Resectable 10% to 20%
Bev + EGFR 1 Randomized Trial Data: OS Trial Treatment Arms OS (months) CAIRO 2 1 : Phase III study to evaluate addition of cetuximab to CT/bevacizumab. CAIRO 2 was not designed dto evaluate the efficacy of bevacizumab b CAIRO-2 1 Cape ox + bevacizumab (n=368) 20.3 Cape ox + bevacizumab b + cetuximab b( (n=368) 19.4 PACCE 2 : Phase IIIB study to evaluate addition of panitumumab to bevacizumab and CT as first line treatment. PACCE was not designed to evaluate the efficacy of bevacizumab PACCE 2 Ox CT + bevacizumab (n=410) Ox CT + bevacizumab + panitumumab (n=413) 24.5 19.4 1. Tol et al. N Engl J Med. 2009;360:563 572. 2. Hecht et al. J Clin Oncol. 2009;27(5):672 680. Back
CALGB 80405: Bevacizumab vs Cetuximab in First line KRAS WT mcrc Untreated KRAS WT mcrc (n=1500) R Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD PD Primary endpoint: OS Secondary endpoints: ORR, PFS, TTF, DOR, andsafety NCT identifier: NCT00265850. 18 18
ADDING CETUXIMAB TO CHEMOTHERAPY IN RESECTABLE CRC LIVER METS PATIENTS
New EPOC Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mcrc Original EPOC study showed 8% PFS benefit to addition of neoadjuvant FOLFOX to surgery in mcrc patients with operable liver metastases [1] New EPOC study evaluated addition of cetuximab to standard neoadjuvant chemotherapy in mcrc [2] Patients with resectable KRAS WT mcrc with liver mets (N = 621) Primary endpoint: PFS Neoadjuvant Chemotherapy* (randomized n = 134; primary analysis n = 116) Neoadjuvant Chemotherapy* h + Cetuximab (randomized n = 137; N = 117) *The majority of patients received FOLFOX Secondary endpoints: OS, preop response, pathologic resection status, periop safety, saey,qo QoL,,cost-effectiveness ec e ess 1. Nordlinger G, et al. Lancet. 2008. 2. Primrose JN, et al. ASCO 2013. Abstract 3504. Used with permission.
Pro oportion Progression free Neoadjuvant Chemotherapy ± Cetuximab in Operable KRAS-WT 1.00 0.75 0.50 0.25 0 Pts at Risk, n Chemo alone 116 Chemo + Cetuximab 117 Chemo alone Chemo + cetuximab mcrc: PFS HR: 1.49 (95% CI: 1.04-2.12; P =.030) 0 6 12 18 24 30 36 42 48 54 60 89 87 65 54 Mos to Progression or Death 38 24 23 15 12 5 5 3 2 2 1 1 1 0 0 0 Median PFS significantly worse with ihcetuximab: 14.1 vs 20.5 mos with chemotherapy alone Study stopped at predefined futility analysis Immature data, but more events unlikely l to change result Primrose JN, et al. ASCO 2013. Abstract 3504. Used with permission.
EGFR FOR CONVERSION THERAPY
CRYSTAL Trial: Liver Resection Increased With Addition of Cetuximab FOLFIRI alone (n = 599) Cetuximab + FOLFIRI (n = 599) Patients (%) 10 9 8 7 6 5 4 3 2 1 0 2.5 ITT Population 6.0 Surgery With Curative Intent OR: 3.0 10 (95% CI: 1.4-6.5; 9 P =.0034) 8 1.5 4.3 No Residual Tumor After Resection Patients (% %) 7 6 5 4 3 2 1 0 Liver Metastases Only Population n = 4.5 134 98 9.8 122 No Residual Tumor in Patients With Liver Metastases Van Cutsem E, et al.
Shanghai h Trial 138 pts with unresectable CRC Liver metastasis Randomized: mfolfox6 OR FOLFIRI Plus cetuximab vs. mfolfox6 OR FOLFIRI alone Treated until deemed resectable or to progression or intolerance Le-chi et al, JCO 31:1931-38, 2013
Shanghai Trial Chemorx plus Regimen cetuximab N 70 Chemorx alone 68 Response rate 57.1% 29.4% 3 year survival 41% 18% Median survival 30.9m 21m All significant at p < 0.05 Le-chi et al, JCO 31:1931-38, 2013
Shanghai Trial R0 resection rate CT + cetux 25.7% CT alone 74% 7.4% Le-chi et al, JCO 31:1931-38, 2013
PRIME: R0 Resection in Pts With WT KRAS Tumors and Liver- Limited Disease Final Analysis Patients with liver-only metastases at baseline, n (%) Pmab + FOLFOX4 FOLFOX4 (n = 325) (n = 331) 61 (19) 57 (17) ORR, % 57 48 Patients with complete liver resection, n (%) 17 (28%) 10 (18%) Douillard JY, et al,.
IS BEVACIZUMAB SAFE IN PATIENTS THAT WILL UNDERGO LIVER METS RESECTION?
Bevacizumab in Potentially Resectable mcrc: No Increase in Complications Patients, n (%) Event All Patients Synchronous Patients (n = 52) No increased bleeding; only 3 patients (n = 11) No complications required blood 42 transfusions (79) (6%) 8 (73) Complications 11 (21) 3 (27) Sepsis 3 (6) 1 (9) Postoperative liver function and Hyperbilirubinemia 2 (4) regeneration normal in 98% of patients Biliary leak 1(2) (assessed perioperatively and 3 mos Postoperative bowel perforation 1 (2) after surgery followed by chemotherapy) Anastomotic leakage 1 (2) 1 (9) Wound infection Hematoma 1(2) 1 (2) 1(9) Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
No Significant Postoperative Complications Following Neoadjuvant Bevacizumab Retrospective analysis of neoadjuvant BEV to evaluate potential association with postoperative complications Patients with colorectal cancer who underwent hepatic surgery for liver metastases Findings No significant increase in hepatobiliary, wound, or other postoperative complications with BEV + CT vs CT alone Day From Last BEV Dose to Surgery Complication 60 Days, % (n = 40) > 60 Days, % (n = 36) P Vl Value Median: 49 days Median: 74 days Any 55 44.43 Wound 33 28.70 Hepatobiliary 8 3.39 Kesmodel SB, et al. J Clin Oncol. 2008;26:5254-5260.
Conclusions Antiangiogenicagents i i t improve outcome in metastatic colon cancer Extended RAS indicated for EGFR inhibitors Cetuximab added to chemotherapy may be detrimental in resectable liver metastasis May play a role in conversion therapy Antiangiogenic agents safe in surgical Antiangiogenic agents safe in surgical patients. At least 6 weeks break suggested.
Mechanisms of Drug Resistance Pretreatment On treatment Progression Epithelial cancer cell Mesenchymal Cancer Stromal RTK cell stem cell cell ligand Lackner MR, et al. Future Oncol. 2012;8(8):999 1014.
OBRIGADO!!!