Tumor Location Prognostic and Predictive in KRAS wt mCRC: Retrospective Analysis of CALGB/SWOG 80405 CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. mCRC, metastatic colorectal cancer; wt, wild type. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

CALGB/SWOG 80405 Substudy: Tumor Location in KRAS wt mCRC CALGB/SWOG 80405 found no significant difference in OS or PFS between cetuximab and bevacizumab when added to first-line FOLFIRI or FOLFOX in pts with RAS wt mCRC[1] Primary tumor location may affect outcome in mCRC Retrospective analysis of data from CALGB/SWOG 80405 evaluated to determine effect of primary tumor location on outcomes in KRAS wt mCRC[5] Study N Molecular Selection Treatment Outcome Mos Tumor Side Right Left O’Dwyer 2001[2] 1120 None 5-FU variations OS 10.9 15.8 Brulé 2015[3] 399 KRAS wt BSC BSC + CET PFS 1.9 1.8 5.4 Loupakis 2015[4] 2027 FOLFIRI/BEV FOLFOX4/XELOX/BEV IFL/BEV 24.8 18.0 14.6 42.0 23.0 20.4 5-FU, 5-fluorouacil; BEV, bevacizumab; BSC, best supportive care; CET, cetuximab; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; FOLFOX4, 5-fluorouracil, foiling acid, oxaliplatin; FU, fluorouracil; IFL, irinotecan/bolus fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; wt, wild type; XELOX, capecitabine plus oxaliplatin. 1. Lenz H, et al. ESMO 2014. Abstract 501O. 2. O’Dwyer PJ, et al. J Clin Oncol. 2001;19: 2413-2421. 3. Brulé SY, et al. Eur J Cancer. 2015;51:1405-1414. 4. Loupakis F, et al. J Natl Cancer Inst. 2015;107:dju427. 5. Venook AP, et al. ASCO 2016. Abstract 3504. Slide credit: clinicaloptions.com

CALGB/SWOG 80405 Substudy: Study Design Retrospective analysis of 1137 pts with KRAS wt mCRC from main CALGB/SWOG 80405 analysis Data extracted from study chart or other available documentation Side of primary tumor determined by colonoscopy, surgical or imaging report Right, n = 293; left, n = 732; transverse/ND, n = 112 Primary objective: evaluate effect of sidedness on OS, PFS in pts with KRAS wt mCRC Exploratory analysis performed in 213 pts with KRAS mutant mCRC mCRC, metastatic colorectal cancer; ND, not determined; wt, wild type. Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2016. Abstract 3504.

CALGB/SWOG 80405 Substudy: Baseline Population Characteristic Overall* (N = 1137) Tumor Side P Value Right (n = 293) Left (n = 732) Mean age, yrs 58.4 61.2 57.3 < .0001 Male, % 62.1 54.9 65.0 .002 Synchronous stage IV, % 79.3 86.9 76.0 .0009 Previous adjuvant therapy, % 14.2 10.6 15.7 .03 FOLFOX/FOLFIRI, % 73.4/26.6 74.4/25.6 72.4/27.6 .51 Primary in place, % 26.6 19.2 29.6 .0007 Metastases pattern, % Liver only Liver metastases Extrahepatic 30.9 42.8 28.5 27.5 40.5 32.0 32.1 43.2 24.7 .02† FOLFIRI, irinotecan/5-fluorouacil/leucovorin; FOLFOX, oxaliplatin/5-fluorouacil/leucovorin; mCRC, metastatic colorectal cancer; wt, wild type. *Side totals excluding 66 pts with tumor in transverse colon and 46 pts with unknown location. †Any liver metastases vs extrahepatic. Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2016. Abstract 3504.

CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for PFS Median PFS, Mos (n = 1025) Primary Tumor Side HR (95% CI) P Value* Right (n = 293) Left (n = 732) All pts 8.9 11.7 1.03 (1.11-1.50) .0006 Cetuximab 7.8 12.4 1.56 (1.26-1.94) < .0001 Bevacizumab 9.6 11.2 1.06 (0.86-1.31) .55 *Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases. Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2016. Abstract 3504.

CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for Overall OS OS prolonged for left-sided vs right-sided tumors Median (95% CI) HR (95% CI) Side N (Events) P Value 100 33.3 (31.4-35.7) 19.4 (16.7-23.6) Left Right 732 (550) 293 (242) 1.55 (1.32-1.82) 80 < .0001 60 OS (%) Left 40 CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival; wt, wild type. Right 20 12 24 36 48 60 72 84 96 108 Mos Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2016. Abstract 3504. Reproduced with permission.

CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for OS by Therapy OS for pts with left-sided tumors is 19.3 mos longer than for right-sided tumors treated with cetuximab[1] Findings consistent with FIRE-3 trial in pts with all RAS wt[2,3] Median OS, Mos (N = 1025) Primary Tumor Side HR (95% CI) P Value* Right (n = 293) Left (n = 732) All pts 19.4 33.3 1.55 (1.32-1.82) < .0001 Cetuximab 16.7 36.0 1.87 (1.48-2.32) Bevacizumab 24.2 31.4 1.32 (1.05-1.65) .01 mCRC, metastatic colorectal cancer; wt, wild type. *Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases. 1. Venook AP, et al. ASCO 2016. Abstract 3504. 2. Stintzing S, et al. ESMO 2013. Abstract E17-7073. 3. Heinemann V, et al. ASCO 2014. Abstract 3600. Slide credit: clinicaloptions.com

CALGB/SWOG 80405 Substudy: Conclusions Location of primary tumor prognostic in KRAS wt mCRC PFS, OS longer in pts with left- vs right-sided tumors Tumor sidedness predictive of response to biologics Markedly longer OS in pts with left-sided tumors treated with first-line chemotherapy + cetuximab vs bevacizumab Pts with right-sided tumors showed greater benefit with first-line chemotherapy + bevacizumab vs cetuximab Investigator conclusions: Sidedness is a surrogate marker for tumor biology Identification of other biomarkers may replace sidedness, help individualize care Pts should be stratified by sidedness in clinical trials mCRC, metastatic colorectal cancer; wt, wild type. Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2016. Abstract 3504.

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