Optimizing Sequencing for Colorectal Cancer What is Best and When? - - PDF document

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Optimizing Sequencing for Colorectal Cancer What is Best and When? - - PDF document

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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

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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
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Stage IV CRC: 2014

1980 1985 1990 1995 2000 2005 2010 Best supportive care Median OS

5-FU

Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab OS (Mos) 30 20 10 1980 1985 1990 1995 2000 2005 Yr 2010 Ziv-aflibercept Regorafenib

Primary Management (Frontline) of Colorectal Cancer

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Colorectal Cancer

Stage IV Colorectal Cancer Clinical Presentation Mutational Status

Resectable : Y Borderline No Ras : Mutant No

54% Survival After Primary or Secondary Resection

  • f Liver Metastases

Survival Time (years)

10 9 8 7 6 5 4 3 2 1

29% 34% 50% 34% 27%

Resectable (n = 425) Initially non resectable (n = 95)

Bismuth et al, 1996

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Yrs 1 2 3 4 5 6 HR: 0.77 (95.66% CI: 0.60-1.00; P = .041) Periop CT 28.1% 36.2% +8.1% at 3 yrs 20 40 60 80 100 Surgery only PFS (%)

EORTC: Resectable Liver Metastases

  • 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.

Tournigand, C. et al. J Clin Oncol; 22:229-237 2004

FOLFOX / FOLFIRI

Colucci, G. et al. J Clin Oncol; 23:4866-4875 2005

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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.

The Lancet Oncology null 2013 null http://dx.doi.org/10.1016/S1470‐2045(13)70154‐2

AVEX: PFS

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FOLFOXIRI as First‐line Therapy

Trial RR, % Median TTP/PFS, Mos Median OS, Mos Souglakos (n = 283) 43.0 vs 33.6 8.4 vs 6.9 21.5 vs 19.5 Falcone (n = 244) 60 vs 34* 9.8 vs 6.9* 22.6 vs 16.7*

Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.

*Statistically significant difference.

Ongoing Trial

CRC Stage IV Previously untreated

FOLFOX +Bev FOLFIRINOX+ Bev m‐FOLFIRINOX +Bev

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Targeting VEGF

Phase III Trial of Bevacizumab + IFL

* PD = progressive disease.

Hurwitz et al. N Engl J Med. 2004;350:2335.

Previously untreated mCRC N=923

Placebo + IFL (n=411) Bevacizumab (5 mg/kg, q2w) + 5-FU/LV (n=110) Bevacizumab (5 mg/kg, q2w) + IFL (n=402) Second-line chemotherapy

± Bev

Second-line chemotherapy ± Bev Second-line chemotherapy, no Bev

PD PD PD

  • Primary endpoint: overall survival
  • Secondary endpoints: PFS, RR, safety, response duration
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Overall Survival

Error bars represent 95% CIs.

Hurwitz et al. N Engl J Med. 2004;350:2335.

100

OS (%) Months Placebo + IFL: 15.6 months Bev + IFL: 20.3 months HR=0.66, P<0.001

1-year survival 74% vs 63% 2-year survival 45% vs 30% 20 80 40 60 6 12 18 24 30

Placebo + IFL (n=411) Bev + IFL (n=402)

Median survival

Bev/Irinotecan‐Based Regimens

Trial AVF2107 (N=411 vs 402) BICC-C (N=57 vs 60) PACE (N=115) Treatment IFL +/‐ Bev Bev+ IFL or FOLFIRI Iri/Bev OS 15.6 vs 20.3 <0.001 28.0 vs 19.2 0.037 20.5 PFS 6.2 vs 10.6 <0.001 11.2 vs 8.3 0.28 11.7 RR 34.8 vs 44.8 57.9 vs 53.3 40%

  • 2. Fuchs , CJ CO2007
  • 3. Hect, JR JCO 2009

1.Hurwitz, H N Engl J Med. 2004;350:2335.

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Bev/Oxaliplatin‐Based Regimens

Trial NO16966 (N=701 vs 699) PACE (410) CARIO 2 (N=375) Treatment FOLFOX/XELOX +/‐ Bev FOLFOX+ Bev XELOX/Bev OS 19.9 vs 21.2 0.077 24.5 20.4 PFS 8.0 vs 9.4 0.0023 On-treatment : 7.9 vs 10.4 <0.0001 11.4 10.7 RR 38 vs 38 48 40

1.Cassidy, J JCO 2008

  • 2. Hecht, JR JCO 2009
  • 3. Tol, J New Eng JM 2009

Targeting EGFR

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Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007

The Ras Mutation

Retrospective Studies: KRAS Interaction With EGFR Inhibitors

Study Regimen N (% mKRAS) RR WT Mutan t Lievre, 2008 Cetuximab 114 (32) 44 De Roock, 2008 CT + Cetuximab 113 (41) 41 Tejpar, 2008 Irinotecan + Cetuximab 89 (36%) 37 Tabernero, 2008 Cetuximab 48 (41) 28 Di Fiore, 2007 CT + Cetuximab 59 (37) 12 Finocchiaro, 2007 Cetuximab ± CT 81 (40) 27 6 Khambata-Ford, 2007 Cetuximab 80 (38) 10 Amado, 2008 Panitumumab 208 (40) 17

  • 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.

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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 PRIME[2‐4] FOLFOX4/Pmab vs FOLFOX4 9.6 vs 8.0 23.8 vs 19.4 FOLFOX4/Pmab vs FOLFOX4 (KRAS/NRAS WT) 10.1 vs 7.9 26.0 vs 20.2 COIN[5] FOLFOX/XELOX/Cetux vs FOLFOX/XELOX 8.6 vs 8.6 17.0 vs 17.9

First Line EGFR‐Targeted Agents

  • 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?

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Analysis of KRAS/NRAS Mutations

Douillard JY, et al. N Engl J Med. 2013;369:1023-1034.

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

CRYSTAL Trial

KRAS WT/BRAF WT (n = 566) KRAS WT/BRAF MT (n = 59) FOLFIRI (n = 289) Cetuximab + FOLFIRI (n = 277) FOLFIRI (n = 33) Cetuximab + FOLFIRI (n = 26) Median OS, mos (95% CI) 21.6 (20.0-24.9) 25.1 (22.5-28.7) 10.3 (8.4-14.9) 14.1 (8.5-18.5) HR (95% CI) P value* 0.830 (0.687-1.004) .0547 0.908 (0.507-1.624) .7440 Median PFS, mos (95% CI) 8.8 (7.6-9.4) 10.9 (9.4-11.8) 5.6 (3.5-8.1) 8.0 (3.6-9.1) HR (95% CI) P value* 0.673 (0.528-0.858) .0013 0.934 (0.425-2.056) 0.8656 OR rate, % (95% CI) 42.6 (36.8-48.5) 61.0 (55.0-66.8) 15.2 (5.1-31.9) 19.2 (6.6-39.4) P value† < .0001 .9136

BRAF Mutation Status

*Stratified log-rank test. †Cochran-Mantel-Haenszel test. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011‐2019.

Median OS: 23 mos Median OS: 23 mos Median OS: 12 mos Median OS: 12 mos

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KRAS status does not impact antiangiogenic therapy outcome No Impact for KRAS status

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0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25

Duration of PFS (Months) Proportion Progression Free

0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25

Duration of PFS (Months) Proportion Progression Free

Mutant KRAS Wild‐Type KRAS

IFL + Placebo 5.5 mo IFL + Bev 9.3 mo IFL + Placebo 7.4 mo IFL + Bev 13.5 mo

HR=0.44; P<0.0001 HR=0.41; P=0.0008

Bevacizumab Shows PFS Benefit Regardless of KRAS Status

  • Rosen. Ann Oncol. 2008;19:vi19 (abstr O‐035).

(n=78) (n=152)

Median PFS Median PFS

VEGFI or EGFRI in Frontline Setting?

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FOLFIRI + Cetuximab

Cetuximab: 400 mg/m2 IV 120 min initial dose 250 mg/m2 IV 60 min q1w

FOLFIRI + Cetuximab

Cetuximab: 400 mg/m2 IV 120 min initial dose 250 mg/m2 IV 60 min q1w

FOLFIRI + Bevacizumab

Bevacizumab: 5 mg/kg IV 30‐90 min q2w

FOLFIRI + Bevacizumab

Bevacizumab: 5 mg/kg IV 30‐90 min q2w

mCRC first‐line therapy KRAS wild‐type (N = 592) mCRC first‐line therapy KRAS wild‐type (N = 592) Randomize 1:1

FIRE‐3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT

  • 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. Heinemann V, et al. ASCO 2013. Abstract LBA3506. Cetuximab + CT Bevacizumab + CT P Value ORR, % (primary endpoint not met) 62 58 .183 PFS, mos 10.0 10.3 .547 Mos Since Start of Treatment Cetuximab + CT (FOLFIRI) Bevacizumab + CT (FOLFIRI) OS Estimate HR: 0.77 P = .017 28.7 mos 25.0 mos 0.75 1.00 0.50 0.25 12 24 36 48 60 72 ∆ = 3.7 mos

FIRE‐3 Trial: FOLFIRI + Either Cetux or Bev in KRAS WT

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Events, n/N (%) Median, Mos 95% CI ― FOLFIRI + cetuximab 91/171 (53.2) 33.1 24.5- 39.4 ― FOLFIRI + bevacizumab 110/171 (64.3) 25.6 22.7- 28.6 HR: 0.70 (95% CI: 0.53-0.92; log-rank P = .011) 171 171 Pts at Risk, n 128 127 71 68 39 26 20 9 6 1 ∆ = 7.5 mos *KRAS and NRAS exon 2, 3, and 4 wild type. 12 24 36 48 60 72 Mos Since Start of Treatment 0.75 1.0 0.50 0.25 Probability of Survival

FIRE‐3: OS in RAS* Wild Type

Stintzing S, et al. ECC 2013. Abstract LBA17.

First‐Line Therapy SWOG/CALGB Intergroup Trial: C80405

mFOLFOX6 Or FOLFIRI Bevacizumab Cetuximab Bevacizumab + Cetuximab Randomize

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CALGB/SWOG 80405: OS in the ITT Population

mOS (95% CI), mos CT + Cetux 29.9 (27.0‐32.9) CT + Bev 29.0 (25.7‐31.2) HR 0.925 (0.78-1.09) P = 0.34

Venook AP, et al. ASCO 2014. Abstract LBA3.

12 24 36 48 60 72 Mos 80 100 60 40 OS (%) 20 84

80405: OS in Systemic Therapy + Surgery

N (Events) mOS, Mos (95% CI) 124 (34) 66.3 (59.8‐NA)

Venook AP, et al. ASCO 2014. Abstract LBA3.

12 24 36 48 60 72 80 100 60 40 OS (%) 20 84 Mos

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CALGB vrs. FIRE‐3

FIRE‐3

  • Superior OS in EGFRI‐ arm
  • Same PFS and RR
  • 100% received FOFIRI
  • Extended Ras mutation

shows increased benefit in favor of EGFRI

CALGB 80405

  • Same OS
  • Same PFS and RR
  • 70% received FOLFOX
  • Extended Ras mutations

pending

Frontline Options

  • Oxaliplatin‐based regimen:

– Bevacizumab plus XELOX or FOLFOX – EGFRI plus FOLFOX (in Extended Ras mutation wild type)

  • Irinotecan‐based regimen:

– Bevacizumab plus FOLFIRI – EFGR I plus FOLFIRI(in Extended Ras mutation wild type)

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Management of Colorectal Cancer Beyond Progression Aflibercept

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VELOUR Study Design

Primary endpoint: overall survival

Metastatic Colorectal Cancer

R A N D O M I Z E

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Placebo IV, day 1 + FOLFIRI q2 weeks 1:1

Disease Progression Death 600 600

Stratification factors:

  • ECOG PS (0 vs 1 vs 2)
  • Prior bevacizumab (Y/N)

Van Cutsem, E JCO 2012

Aflibercept + FOLFIRI (n=612) Placebo + FOLFIRI (n=614) HRa=0.82 (95.34% CI, 0.71‐0.94) P=0.0032

OS Estimate Time, Months

0.2 0.8 0.4 1.0 0.6 6 12 3 9 15 21 27 18 24 30 36 33 39 12.1 mos 13.5 mos

Overall Survival

VELOUR : Overall Survival (OS) in ITT Population

Van Cutsem, E JCO 2012

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AE, Safety Population Placebo + FOLFIRI, % (n=605) Aflibercept + FOLFIRI, % (n=611) All Grades Grade 3/4 All Grades Grade 3/4 Diarrhea 56.5 7.8 69.2 19.3 Neutropeniaa Complicated neutropenia 56.3 – 29.5 2.8 67.8 – 36.7 5.7 Asthenic conditions (HLT) 50.2 10.6 60.4 16.9 Stomatitis and ulceration (HLT) 34.9 5.0 54.8 13.7 Thrombocytopeniaa 33.8 1.7 47.4 3.3 Infections (SOC) 32.7 6.9 46.2 12.3 Decreased appetite 23.8 1.8 31.9 3.4 Weight decreased 14.4 0.8 31.9 2.6 Palmar plantar erythrodysesthesia 4.3 0.5 11.0 2.8 Skin hyperpigmentation 2.8 8.2 Dehydration 3.0 1.3 9.0 4.3

VELOUR Most Frequent AEs

Van Cutsem, E JCO 2012

Bevacizumab

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BEV + standard first-line CT (n=820)

Randomise 1:1

Standard second- line CT BEV + standard second- line CT

PD

TML‐1 Design

CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin

Primary endpoint

  • Overall survival (OS) from randomisation

Secondary endpoints included

  • Progression-free survival (PFS)
  • Best overall response rate
  • Safety
  • Stratification factors
  • First-line CT (oxaliplatin-based, irinotecan-based)
  • First-line PFS (≤9 months, >9 months)
  • Time from last BEV dose (≤42 days, >42 days)
  • ECOG PS at baseline (0/1, 2)

Bennouna, J Lancet 2013

OS: ITT population

OS estimate

Time (months)

1.0 0.8 0.6 0.4 0.2 6 12 18 24 30 36 42 48 CT (n=410) BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

Bennouna, J Lancet 2013

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PFS: ITT population

PFS estimate Time (months) 1.0 0.8 0.6 0.4 0.2 6 12 18 24 30 36 42 CT (n=410) BEV + CT (n=409)

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test) Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test)

Bennouna, J Lancet 2013

Both VELOUR and TML suggest that continuing antiangiogenic therapy beyond progression is beneficial

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EGFR‐I Second‐line Therapy With EGFRI

Trial Comparative Regimens PFS, Mos OS, Mos EPIC[1] Irinotecan/Cetux vs Irinotecan 4.0 vs 2.6* 10.7 vs 10.0 181[2] FOLFIRI/Pmab vs FOLFIRI 5.9 vs 3.9* 14.5 vs 12.5 SPIRITT[3] FOLFIRI/Pmab vs FOLFIRI/Bev 7.7 vs 9.2 18.0 vs 21.4 PICCOLO[4] Irinotecan/Pmab vs Irinotecan HR: 0.78† 10.9 vs 10.4

  • 1. Sobrero AF, et al. J Clin Oncol. 2008;26:2311-2319. 2. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.
  • 3. Hecht JR, et al. ASCO 2013. Abstract 335. 4. Seymour MT, et al. Lancet Oncol. 2013;14:749-759.

*Statistically significant difference. Retrospective KRAS analysis (< 25% of pts enrolled).

†P = .015

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Cetuximab: Pivotal Trial

  • ERBITUX initial dose: 400 mg/m2 (2-hr IV)
  • Maintenance dose: 250 mg/m2 weekly (1-hr IV)
  • Irinotecan: same dose and schedule as

patients had previously failed

Patients with EGFR-expressing mCRC who progressed after irinotecan-based chemotherapy 2:1 Randomization ERBITUX + irinotecan (n = 218) Stratification

  • Performance

status

  • Prior oxaliplatin
  • Treatment center

Crossover after progression ERBITUX single agent (n = 111)

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

Cetuximab: Combination With Irinotecan Time to Progression, All Patients (N = 329)

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Subsequent lines RAS Wild type‐1

  • Switch chemotherapy backbone

– FOLFOX to FOLFIRI – FOLFIRI to FOLFOX

AND

  • Switch or continue Monoclonal antibody

– EGFRI to Bevacizumab – Bevacizumab to EGFR I or Aflibercept – Bevacizumab continue Bev

Subsequent lines RAS Wild type‐2

  • Keep same chemotherapy backbone

– FOLFIRI

AND

  • Switch or continue Monoclonal antibody

– Bevacizumab to EGFR I

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Subsequent lines RAS Mutated

  • Switch chemotherapy backbone

– FOLFOX to FOLFIRI – FOLFIRI to FOLFOX

AND

  • Switch or continue Monoclonal antibody

– Bevacizumab to Aflibercept – Bevacizumab continue Bev

When all else fails….Regorafenib

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Regorafenib: an oral multikinase inhibitor1‐3

KIT PDGFR

RET

  • 1. Wilhelm SM et al. Int J Cancer 2011.
  • 2. Mross K et al. Clin Cancer Research 2012.
  • 3. Strumberg D et al. Expert Opin Invest Drugs 2012.

PDGFR-β FGFR VEGFR1-3 TIE2

Regorafenib Inhibition of neoangiogenesis Inhibition of neoangiogenesis Inhibition of tumor microenvironment signaling Inhibition of tumor microenvironment signaling Inhibition of proliferation Inhibition of proliferation Biochemical activity Regorafenib IC50 mean ± SD nmol/l (n)

VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAFV600E 19 ± 6 (6)

CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy

2:1

Evaluation with CT scan of abdomen and chest every 8 weeks

Grothey, A Lancet 2013

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Overall survival (primary endpoint)

Grothey, A Lancet 2013

Progression‐free survival

Grothey, A Lancet 2013

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Overall response and disease control rates

Best response, % Regorafenib N=505 Placebo N=255 Complete response PR 1.0 0.4 SD 42.8 14.5 Progressive disease 49.5 80.0 DCR* 41.0 14.9

*DCR = PR + SD (≥6 weeks after randomization); p<0.000001

Regorafenib significantly improves DCR compared to placebo Grothey, A Lancet 2013

Adverse Events

Adverse event, % Regorafenib N=500 Placebo N=253 All grades Grade 3 Grade 4 Grade 5* All grades Grade 3 Grade 4 Grade 5* Hand-foot skin reaction 46.6 16.6 7.5 0.4 Fatigue 47.4 9.2 0.4 28.1 4.7 0.4 Hypertension 27.8 7.2 5.9 0.8 Diarrhea 33.8 7.0 0.2 8.3 0.8 Rash / desquamation 26.0 5.8 4.0 Anorexia 30.4 3.2 15.4 2.8 Mucositis, oral 27.2 3.0 3.6 Thrombocytopenia 12.6 2.6 0.2 2.0 0.4 Fever 10.4 0.8 2.8 Nausea 14.4 0.4 11.1 Bleeding 11.4 0.4 0.4 2.8 Voice changes 29.4 0.2 5.5 Weight loss 13.8 2.4

Grothey, A Lancet 2013

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Colorectal Cancer‐Future Questions

  • Need better biomarkers to decide on how to

select the targeted agents.

  • Where does the EGFR blocker fit in the KRAS

wild type?

– Frontline vs. refractory disease

  • Potentially resectable stage IV disease – is

there a role for targeted agents?

Thank You