Alan P. Venook, MD University of California, SF GREAT DEBATE: CRC FIRST-LINE TREATMENT Alan P. Venook, MD University of California, SF

Presented by:

CRC ESMO GUIDELINES

Cytotoxic backbone: Usage patterns FOLFOX preferred in US CALGB/SWOG 80405: 74% choose FOLFOX 2nd line trials almost all use irinotecan-based rx FOLFIRI use likelier in parts of Europe FOLFOXIRI not yet broadly accepted Fluoropyrimidine alone in poor KPS patients

EGF-R VEGF

CALGB/SWOG 80405: FINAL DESIGN mCRC 1st-line KRAS wild type (codons 12,13) STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT FOLFIRI or FOLFOX MD choice Chemo + Cetuximab Chemo + Bevacizumab N = 1140 1° Endpoint: Overall Survival

CALGB/SWOG 80405: Overall Survival Arm N (Events) OS (m) Median 95% CI Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 P=0.34 HR 0.925 (0.78-1.09)

RAS mutations: CALGB/SWOG 80405 670/1137 patients (59%) with KRAS codon 12/13 WT tumors evaluable for tumor RAS status; 621/1137 analyzed (55%) RAS mutations (%): 95/621 (15.3%) patients KRAS† EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 WT +1.3% 1.8% 5.9% NRAS†* EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 2.3% 4.2% 0% †Percentages relate to fraction of RAS evaluable patients with mutations in particular exons; *One patient had a mutation at both NRAS Exon1 codon12 and NRAS Exon3 codon61

Overall Survival By Arm (All RAS Wild Type Patients) (Events) Median (95% CI) HR p Chemo + Bev 256 (178) 31.2 (26.9-34.3) 0.9 (0.7-1.1)   0.40 Chemo + Cetux 270 (177) 32.0 (27.6-38.5)

Quality of Life and Symptoms Hypotheses: Cetuximab will reduce satisfaction with appearance and diminish overall quality of life Measures: EORTC QLQ-C30 Dermatology-Specific Quality of Life (DSQL) Assessment Timepoints: Baseline, 6 weeks, 3, 6 and 9 months Presented by:

Slide courtesy of Dueck, Schrag, Naughton EORTC GLOBAL QOL DSQL SKIN SATISFACTION ------- BEVACIZUMAB ------- CETUXIMAB Slide courtesy of Dueck, Schrag, Naughton Presented by:

Different results from FIRE-3 CRITICISMS OF 80405 Some results still pending / unaudited Expanded RAS / RR to be updated Not all data captured Sidedness / subsequent therapies / CEA No Central Radiology review Depth of response / time to response Different results from FIRE-3

FIRE-3 v CALGB/SWOG 80405 RAS status / FOLFIRI comparison FOLFIRI backbone RAS status FIRE 3 BEV v CETUX CALGB/SWOG 80405 PFS 10.3 v 10.0 mos 11.6 v 10.3 mos OS 25.0 v 28.7 mos HR: 0.77 (p=0.017) 33.4 v 28.9 mos HR: 0.92 (p=0.34) 10.2 v 10.4 mos 11.9 v 12.7 mos 25.6 v 33.1 mos HR: 0.70 (p=0.011) 35.2 v 32.0 mos HR: 0.90 (p=0.7) KRAS WT codons 12, 13 ALL RAS WT

CRITICISMS OF FIRE-3 1° endpt: Response Rate (Investigator) RR differential increased w/ central review Small % pts receive 2nd line biologic Data presented with shrinking denominator Bev pts OS nearly 10 months less

New EPOC: PFS and OS Primrose, et al, Lancet Oncol, 2014 2014. PFS: 20.5 mos v. 14.1 mos OS: NR v 39.1 Primrose, et al, Lancet Oncol, 2014 2014.

WHAT SEEMS TO BE SETTLED? EGFR arms similar across studies All RAS analysis separates patients: May benefit from EGFR Ab (45%) Do not benefit and poorer prognosis (55%) NEW EPOC outliers Pts in Europe get less benefit from BEV NO obvious explanation for differences between FIRE-3 and 80405

PATIENTS HAVE A CHOICE marketing, taste, bias