Prognostic Factors for First-line Chemotherapy + Bevacizumab or Cetuximab in Metastatic Colorectal Cancer CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals mCRC, metastatic colorectal cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

CALGB/SWOG 80405 Prognostic Factors: Background Tumor biology, including sidedness, has been correlated with prognosis in mCRC[1] Somatic mutation analysis via NGS may identify genetic alterations associated with prognosis in solid tumors[2] Phase IIII CALGB/SWOG 80405 trial demonstrated no significant difference in OS, PFS with cetuximab vs bevacizumab addition to first-line FOLFOX or FOLFIRI in pts with KRAS wild-type mCRC[3] mOS, cetuximab vs bevacizumab: 29.9 vs 29.0 mos; mPFS: 10.4 vs 10.8 mos mOS, left-sided vs right-sided tumors: 33.3 vs 19.4 mos; P < .0001[4] Current subanalyses of CALGB/SWOG 80405 evaluated sidedness (independent of molecular features)[5] and genetic markers[6] as prognostic indicators in pts with mCRC CT, chemotherapy; FOLFIRI, fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin; m, median; mCRC, metastatic colorectal cancer; NGS, next-generation sequencing; SOC, standard-of-care. 1. Holch JW, et al. Eur J Cancer. 2017;70:87-98. 2. Yu B, et al. Transl Pediatr. 2015;4:125-138. 3. Venook A, et al. JAMA. 2017. In press. 4. Venook AP, et al. ASCO 2016. Abstract 3504. 5. Venook AP, et al. ASCO 2017. Abstract 3503. 6. Innocenti F, et al. ASCO 2017. Abstract 3504. Slide credit: clinicaloptions.com

CALGB/SWOG 80405: Study Design and Survival Randomized, open-label phase III trial No difference between cetuximab and bevacizumab when combined with FOLFIRI or FOLFOX with respect to OS or PFS[1] OS, Mos PFS, Mos 29.9 10.4 29.0 10.8 Pts with KRAS wild-type (Codons 12, 13) metastatic/advanced CRC and no previous therapy for advanced disease (N = 1137) Cetuximab + Chemotherapy* (n = 578) Bevacizumab + Chemotherapy* (n = 559) *Physician choice of FOLFIRI or FOLFOX. CRC, colorectal cancer; FOLFIRI, fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin. 1. Venook A, et al. JAMA. 2017 (in press). 2. Venook A, et al. ASCO 2017. Abstract 3503. 3. Innocenti F, et al. ASCO 2017. Abstract 3504. Slide credit: clinicaloptions.com

CALGB/SWOG 80405 Prognostic Factors: Current Analyses Multivariate analysis of prognostic utility of tumor sidedness (independent of other molecular features)[1] Evaluated in subset of pts with left-/ right-sided tumors (no transverse) and available molecular data (n = 728) Used Cox proportional hazard models* Evaluated potential biomarkers of sidedness/tumor burden Analysis of mutational profile and prognostic, clinical value of DNA alterations[2] DNA from 504 tumor specimens Mutation profile determined by PCR genotyping in 12 genes, MSI-high status by microsatellite mutation analysis, mutational load in 395 genes by NGS Primary endpoint: OS Used Cox proportional hazard models* to test association with molecular alterations† CT, chemotherapy; MSI, microsatellite instability; NGS, next-generation sequencing; RT, radiation therapy. *Models stratified by adjuvant CT, prior RT. Models adjusted for age, race, sex, synchronous vs metachronous, BRAF. Sidedness analysis also adjusted for consensus molecular subtypes, MSI, NRAS, KRAS, HRAS; mutational analysis for liver metastases only, sidedness. †No adjustment for multiple comparisons. Slide credit: clinicaloptions.com 1. Venook AP, et al. ASCO 2017. Abstract 3503. 2. Innocenti F, et al. ASCO 2017. Abstract 3504.

OS by Side and Treatment CALGB/SWOG 80405 Prognostic Factors: OS by Side of Tumor and Biologic Treatment Pts with right-sided tumor, n = 293 (27%); left-sided, n = 732 (68%) Pts with transverse colon tumors excluded from analysis (n = 66) OS by Sidedness OS by Side and Treatment Side Left Right mOS (95% CI) 33.3 (31.4-35.7) 19.4 (16.7-23.6) N (Events) 732 (550) 293 (242) HR 1.55 (1.32-1.82) P Value < .0001 Left/Bevacizumab mOS 31.4 (95% CI: 28.3-33.6) Left/Cetuximab mOS 36.0 (95% CI: 32.6-40.3) Right/Bevacizumab mOS 24.2 (95% CI: 17.9-30.3) Right/Cetuximab mOS 16.7 (95% CI: 13.1-19.4) 100 100 80 80 60 60 OS (%) OS (%) 40 Bev, bevacizumab; Cet, cetuximab. Left 40 Right 20 20 12 24 36 48 60 72 84 96 108 12 24 36 48 60 72 84 96 108 Mos Mos Slide credit: clinicaloptions.com Venook A, et al. ASCO 2016. Abstract 2016. Reproduced with permission.

Right-Sided Tumors (n = 167) Left-Sided Tumors (n = 330) CALGB/SWOG 80405 Prognostic Factors: Sidedness Independent of Molecular Features Multivariate analysis found that sidedness a significant prognostic factor independent of other molecular features HR: 1.392 (95% CI: 1.032-1.878; P = .031*) Clinical characteristics compared between pts with right- vs left-sided tumors to determine whether sidedness potentially a surrogate for tumor burden Pattern of metastases significantly differed by side (Chi-squared P = .0136) No significant differences with other tumor burden indicators Tumor Burden Indicator, % Right-Sided Tumors (n = 167) Left-Sided Tumors (n = 330) Median LDH, IU/L 195.5 196.5 Metastatic sites, n 1 2 ≥ 3 53.9 33.9 11.5 55.9 30.1 13.1 Prior adjuvant tx 12.0 18.8 1⁰ in place at tx initiation 4.8 1.8 Intent, palliative/curative 86.4/13.6 83.1/16.9 Pattern of metastases Liver only Liver + extrahepatic Extrahepatic only 30.3 62.4 37.0 38.3 73.3 25.8 LDH, lactate dehydrogenase; tx, treatment. *Per stratified, adjusted Cox proportional hazard model. Slide credit: clinicaloptions.com Venook AP, et al. ASCO 2017. Abstract 3503.

Pts With NGS and Mutational Load Data CALGB/SWOG 80405 Prognostic Factors: Pt Characteristics for Genetic Analysis Characteristics, n (%) Pts With 12-Gene Data (n = 504) Pts With NGS and Mutational Load Data (n = 293) Male 313 (62) 191 (65) Treated with cetuximab Treated with bevacizumab 248 (49) 256 (51) 163 (56) 130 (44) Synchronous tumor growth Metachronous tumor growth 393 (78) 110 (22) 236 (81) 56 (19) Metastases in liver, only Metastases in other than liver 322 (64) 179 (36) 178 (61) 112 (39) Tumor on right or transverse colon Tumor on left colon 183 (39) 285 (61) 103 (38) 167 (62) NGS, next-generation sequencing. Slide credit: clinicaloptions.com Innocenti F, et al. ASCO 2017. Abstract 3504.

CALGB/SWOG 80405 Prognostic Factors: OS by BRAF Genotype Patient Genotype Group Median OS, Mos (95% CI) HRadj (95% CI) P for Interaction, BRAF/biologics BRAF genotype Wild type (n = 432) Mutant (n = 72) 34.2 (31.0-36.4) 12.9 (11.1-19.0) 1.82 (1.37-2.44) P = .0001* BRAF wild type Treated with cetuximab (n = 225) Treated with bevacizumab (n = 207) 33.4 (29.1-39.2) 34.4 (30.3-37.6) 0.97 (0.77-1.23) P = .75 .13 BRAF mutant Treated with cetuximab (n = 31) Treated with bevacizumab (n = 41) 11.7 (8.6-19.7) 15.0 (11.8-23.7) 0.61 (0.35-1.06) P = .51 adj, adjusted. *If further adjusted for sidedness of tumor, HR: 1.67 (95% CI: 1.20-2.33; P = .0035). Slide credit: clinicaloptions.com Innocenti F, et al. ASCO 2017. Abstract 3504.

CALGB/SWOG 80405 Prognostic Factors: OS by MSI Status Patient Subgroup Median OS, Mos (95% CI) HRadj (95% CI) P for Interaction, MSI/biologics Microsatellite instability High level of instability (n = 29; 52% BRAF mutant) Stable (n = 389; 11% BRAF mutant) 30.3 (22.6-NE) 31.8 (29.0-35.2) 0.84 (0.51-1.39) P = .50 Microsatellite stable Treated with cetuximab (n = 224) Treated with bevacizumab (n = 220) 33.4 (29.1-39.3) 32.8 (29.0-36.0) 1.03 (0.82-1.30) P = .48 .0002 Microsatellite instability-high Treated with cetuximab (n = 13, 46% BRAF mutant) Treated with bevacizumab (n = 18, 61% BRAF mutant) 11.5 (10.3-NE) 30.3 (23.6-NE) 0.17 (0.07-0.41) P = .002 adj, adjusted; MSI, microsatellite instability; NE, not evaluable. Slide credit: clinicaloptions.com Innocenti F, et al. ASCO 2017. Abstract 3504.

CALGB/SWOG 80405 Prognostic Factors: OS by Mutational Load Patient Subgroup Median OS, Mos (95% CI) HRadj (95% CI) P for Interaction, Mutational Load/Biologics Mutational Load in MSS mCRC ≤ 8 (n = 228) > 8 (n = 65) 30.1 (25.6-34.3) 35.7 (31.2-45.5) 0.67 (0.47-0.95) P = .02 Mutational Load ≤ 8 in MSS mCRC Treated with cetuximab (n = 103) Treated with bevacizumab (n = 125) 29.1 (24.3-38.5) 30.3 (25.3-34.5) 1.00 (0.72-1.39) P = .97 .56 Mutational Load > 8 in MSS mCRC Treated with cetuximab (n = 27) Treated with bevacizumab (n = 38) 35.8 (30.3-63.7) 35.1 (31.2-53.6) 0.81 (0.43-1.52) P = .79 adj, adjusted; mCRC, metastatic colorectal cancer; MSS, microsatellite stable. Slide credit: clinicaloptions.com Innocenti F, et al. ASCO 2017. Abstract 3504.

CALGB/SWOG 80405 Prognostic Factors: Investigator Conclusions In pts with mCRC and no previous therapy for advanced disease: Left-sided tumors significantly associated with improved OS, regardless of biologic tx[1] Sidedness a prognostic factor independent of other molecular features (HR: 1.392; P = .031) Investigators concluded that tumor sidedness differences not due to tumor burden; further study warranted to identify mechanisms behind sidedness as independent prognostic factor BRAF status strong prognostic marker, even when adjusted for tumor sidedness, but has no predictive interaction with biologic therapy[2] MSI status not prognostic but may be predictive for biologic therapy[2] Mutational load in pts with MSS CRC has prognostic potential but does not seem to be predictive for biologic therapy[2] According to investigators, these data indicate that pt and tumor characteristics may help predict response to biologic therapy but larger numbers of pts and more markers need to be explored[1,2] CRC, colorectal cancer; mCRC, metastatic colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; tx, treatment. Slide credit: clinicaloptions.com 1. Venook AP, et al. ASCO 2017. Abstract 3503. 2. Innocenti F, et al. ASCO 2017. Abstract 3504.

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