1. Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy

2. Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy
Jimmy Hwang, MD
Associate Professor, Hematology/Oncology
John L. Marshall, MD
Department of Medicine
Lombardi Cancer Center
Georgetown University Hospital
Washington, DC

3. Colorectal Cancer: Epidemiology
Data from the United States (2006)[1]
148,610 new cases: third highest cancer incidence
55,170 deaths: second leading cause of cancer-related death in men, third leading cause in women
Worldwide (2002)[2]
1,023,256 new cases: third highest incidence after lung, breast cancer
529,020 deaths: fourth overall cause of cancer-related death after lung, gastric, liver cancer
1. Jemal A, et al. CA: Cancer J Clin. 2006;56: Kamangar F, et al. J Clin Oncol. 2006; 24:

4. Pathophysiology of Colorectal Cancer
Normal colonic epithelial cells transformed by histopathologic, molecular events
Adenomatous polyps
Intermediate stage in carcinogenic process
Polyps occur in 33% of general population by age 50
50% incidence by age 70
Genetic basis for adenoma transformation to colorectal cancer
Mutations in APC, K-ras, at earlier, nonmalignant stages
p53 mutation appears to trigger malignancy
Janne PA, et al. N Engl J Med. 2000;342: Vogelstein B, et al. N Engl J Med. 1988;319:

5. The Adenoma-Carcinoma Process
Mutations leading to formation of colorectal tumor
Normal colonic epithelium
Mutation in APC
Dysplastic aberrant crypt foci
Initial adenoma develops
Mutation in K-ras
Intermediate adenoma
Mutation in DCC
Late adenoma
Mutation in p53
Carcinoma
Other alteration?
Metastasis
Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998: Vogelstein B, et al. N Engl J Med. 1988;319: Fearon ER, et al. Cell. 1990;61:

6. Screening and Cancer Prevention
Screening with colonoscopy may detect precancerous polyps and other early-stage disease[1]
Recommended beginning at age 50, every 10 years
May begin at 40 years for patients at increased risk
Aspirin, cyclooxygenase-2 (COX-2) inhibitors associated with reduction in incidence of colorectal adenomas[2,3]
Despite these techniques, ~ 25% of patients present with metastatic disease[4]
Nearly one half of patients with colorectal cancer require systemic therapy
1. Regula J, et al. N Engl J Med. 2006;355: Baron JA, et al. N Engl J Med. 2003;348: Bertagnolli MM, et al. N Engl J Med. 2006;355:

7. Chemotherapy for Metastatic Colorectal Cancer
Thymidylate synthase inhibitors
Fluoropyrimidines: 5-FU (intravenous), capecitabine (oral)
Raltitrexed
Topoisomerase I inhibitors
Irinotecan
Alkylating agents
Oxaliplatin
Traditional 5-FU–based chemotherapy associated with modestly improved survival
Newer agents (ie, irinotecan, oxaliplatin) lengthen survival outcomes

8. Fluoropyrimidines in Metastatic Disease
No increase in survival benefit regardless of schedule
Median survival: ~ 12 months
Regimen
Response, %
Bolus 5-FU
7-15
Infusional 5-FU
20-30
5-FU/LV
Mayo, Roswell schedules
de Gramont (LV5-FU2)
AIO (once weekly, 24-hour infusion)
12-35
28-33
25-44
Capecitabine
20-25
5-FU, fluorouracil; AIO, Arbeitsgemeinschaft Internische Onkologie; LV, leucovorin.
Grothey A, et al. J Clin Oncol. 2005;23:

9. Multiple Active Agents Associated With Increased Survival
Combinations of multiple active agents associated with better outcome
5-FU, irinotecan, oxaliplatin
Compared with 5-FU/LV, use of all 3 active therapies associated with improved survival
Median survival with triple-drug regimens: ~ 20 months
First-line doublet chemotherapy
Associated with increased exposure to all 3 active agents during therapeutic course
Grothey A, et al J Clin Oncol. 2005;23:

10. Chemotherapy Efficacy Plateau
Median survival with addition of newer agents appears to plateau at 20 months
Combination Therapy
Active Agents
Median Survival, mos
5-FU/LV
1 drug
11-12
Irinotecan/5-FU
2 drugs
14-15
Oxaliplatin/5-FU ± irinotecan
3 drugs
17-20
Meta-analysis Group in Cancer. J Clin Oncol. 1998;16: Saltz LB, et al. N Engl J Med 2000;343: de Gramont A, et al. J Clin Oncol. 2000;18: Goldberg RM, et al. J Clin Oncol. 2002;20: Tournigand C, et al. J Clin Oncol. 2004;22:

11. Molecular Targets in Metastatic Colorectal Cancer
Epidermal growth factor receptor (EGFR)
Vascular endothelial growth factor receptor (VEGFR)
COX-2
Other targets
Carcinoembryonic antigen
Protein kinase C
Matrix metalloproteinases
Ras
Cyclin dependent kinase

12. EGFR Inhibitors in Colorectal Cancer
EGFR overexpression found in up to 90% of metastatic tumors
Activation of EGFR ultimately results in inhibition of apoptosis, malignant cell proliferation, migration, and angiogenesis
EGFR-expressing tumors more aggressive with worse prognosis
Monoclonal antibodies targeting EGFR
Cetuximab, panitumumab
Tyrosine kinase inhibitors (TKIs) of EGFR
Gefitinib, erlotinib
Venook A. Oncologist. 2005;10: Mayer A, et al. Cancer. 1993;71:

13. EGFR Inhibitors in Colorectal Cancer (cont’d)
To date, few promising results with EGFR-targeted TKIs in colorectal cancer setting
Phase II gefitinib study in 110 patients with refractory disease[1]
2 doses studied, only 1 response noted in higher-dose (500 mg) group
No objective responses noted in study of erlotinib in second-line setting[2]
To date, monoclonal antibodies have exhibited better activity in metastatic disease
1. Rothenberg ML, et al. J Clin Oncol. 2005;23: Townsely CA, et al. Br J Cancer. 2006;94:

14. Cetuximab ± Irinotecan: The BOND Study
Irinotecan dose and schedule used during progression Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week (n = 218)
Patients with progressive colorectal cancer on or within 3 months of irinotecan-based chemotherapy
(N = 329)
Irinotecan dose and schedule used during progression Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week
Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week
(n = 111)
Irinotecan regimens: 126 mg/m2 for 4 weeks alone or combined with 5-FU/LV; 180 mg/m2 plus 5-FU/LV, every 2 weeks; 350 mg/m2, every 3 weeks PD
PD, progressive disease.
Primary endpoint: response.
Cunningham D, et al. N Engl J Med. 2004;351:

15. The BOND Study: Efficacy
Improved response, disease control, median TTP with irinotecan + cetuximab
Irinotecan +
Cetuximab
Cetuximab Alone
P Value
PR, % (95% CI)
22.9 ( )
10.8 ( )
.0074
Disease control*,% (95% CI)
55.5 ( )
32.4 ( )
.0001
Median TTP, mos
4.1
1.5
< .0001
Median survival, mos (95% CI)
8.6 ( )
6.9 ( )
.48
PR, partial response; TTP, time to progression
*Disease control = complete and partial responses + stable disease.
Cunningham D, et al. N Engl J Med. 2004;351:

16. Bevacizumab/Cetuximab + Irinotecan* Bevacizumab/Cetuximab*
The BOND-2 Study
Bevacizumab/Cetuximab + Irinotecan*
Cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly
Bevacizumab 5 mg/kg every other week
Irinotecan at same dose and schedule given just before study entry
(n = 41)
Metastatic
colorectal cancer
patients refractory
to irinotecan
(N = 81)
Bevacizumab/Cetuximab*
Cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly
Bevacizumab 5 mg/kg every other week
(n = 40)
*Patients received cetuximab on Day 1 (plus irinotecan, if randomized to that arm) and bevacizumab on Day 2.
Saltz L, et al. ASCO Abstract 3508.

17. BOND-2 Efficacy Results
Significant response for bevacizumab + cetuximab
Addition of irinotecan improved responses
Bevacizumab extends time to tumor progression vs historical controls
Median TTP
100
CET/BEV
CET/IRI/BEV
CET/BEV
CET/IRI/BEV
CET*
CET/IRI*
CET*
CET/IRI* 80 60
P = .03
5.6
Partial Response (%)
P < .01
1.5
P = .05 37 40 23
7.9
P < .01 23
4.0 20 11 2 4 6 8 10 12
*Historical controls.
Time to Tumor Progression (Mos)
Saltz L, et al. ASCO Abstract 3508.

18. BOND and BOND-2: Safety
BOND: overall incidence of adverse events higher in cetuximab-irinotecan arm; 65% vs 44%; P < .001
Diarrhea, neutropenia more common with combination therapy
Acne-like rash in 80% of patients in each treatment arm
Rash appeared within first 3 weeks of cetuximab treatment in majority of cases (89%)
BOND-2: no synergistic toxicity noted for combined therapies
No antibody-related grade 3 allergic reactions; 17% to 20% incidence of antibody-related grade 3 rash
Most common irinotecan-related toxicity; grade 3/4 diarrhea (24%), neutropenia (22%)
Cunningham D, et al. N Engl J Med. 2004;351: Saltz L, et al. ASCO Abstract 3508.

19. CALGB 80203: Study Design
Cetuximab 400 mg/m2 loading dose, then 250 mg/m2 once weekly (n = 55)
Placebo (n = 58)
FOLFOX Oxaliplatin 85 mg/m2 Days 1, 8 LV 20 mg/m2 over 2 hours Days 1, 8 5-FU 500 mg/m2 bolus, Days 1, 8 every 3 weeks
Patients with untreated metastatic colorectal cancer
(N = 238)*
Cetuximab 400 mg/m2 loading dose, then 250 mg/m2 once weekly (n = 55)
Placebo (n = 58)
FOLFIRI Irinotecan 180 mg/m2 Day 1 LV 400 mg/m2 over 2 hours Day 1 5-FU 400 mg/m2 bolus, then mg/m2 46-hour infusion Days 1-2 every 3 weeks
Primary endpoint: OS. Secondary endpoints: PFS, RR.
*Original accrual goal of 2200 patients; after bevacizumab received FDA approval, study closed and redesigned in January 2005 as phase II randomized trial.
Venook A, et al. ASCO Abstract 3509.

20. CALGB 80203: Preliminary Data
PFS, OS: more follow-up needed
Addition of cetuximab appears to increase response
Response, %
FOLFOX + Cetuximab
FOLFIRI + Cetuximab
FOLFOX
FOLFIRI
ORR (CR + PR) 60 44 40 36
CR, complete response; ORR, overall response rate; PR, partial response
Response, % (P = .029)
Chemotherapy + Cetuximab
Chemotherapy Alone
ORR (CR + PR) 52 38
Venook A, et al. ASCO Abstract 3509.

21. CALGB/SWOG 80405: Study Design
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weekly
Patients with untreated metastatic colorectal cancer
(N = 2289)*
Patient/physician choice: mFOLFOX6 or FOLFIRI
Bevacizumab 5 mg/kg IV every 2 weeks
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weekly Bevacizumab 5 mg/kg IV every 2 weeks
Primary endpoint: OS. Secondary endpoints: PFS, RR.
*~300 patients enrolled as of November 2006.
Study open through CTSU.org

22. Panitumumab in Colorectal Cancer
Activity in phase II studies
Panitumumab 2.5 mg/kg weekly in 148 previously treated patients
PR: 9%; SD: 29%
PFS: 3.1 mos; OS: 9.4 mos
Panitumumab combined with first-line IFL (n = 19), FOLFIRI (n = 24)
Well tolerated in combination with FOLFIRI
PR: 33%; SD: 46%
Based on these results, phase III study conducted
Malik I, et al. ASCO 2005 Abstract Hecht J. ASCO GI Abstract 237.

23. Panitumumab vs BSC in Metastatic Colorectal Cancer
Panitumumab 6 mg/kg every 2 weeks +
BSC
(n = 231)
Patients with metastatic colorectal cancer who failed prior standard chemotherapy
(N = 463)
BSC*
(n = 232)
Stratification by ECOG score (0-1 vs 2) and geographic locale
BSC, best supportive care.
*Patients who experienced progressive disease eligible for crossover to panitumumab in optional, separate trial.
Peeters M, et al. AACR Abstract CP-1.

24. Panitumumab vs BSC: Main Findings
PFS significantly better for panitumumab-treated patients*
HR: 0.54 (95% CI: ; P < ) 50
Panitumumab + BSC 40
BSC 30
Progression Free (%) 20 10
*Median follow-up: 19 weeks. 1 1 49 30 35 14 26 9 18 5 10 4 4 1
Wk 8
Wk 12
Wk 16
Wk 24
Wk 32
Wk 40
Wk 48
Peeters M, et al. AACR Abstract CP-1.

25. Panitumumab vs BSC: Main Findings (cont’d)
Panitumumab efficacy consistent across all subgroups
42% of 174 BSC patients who switched over to separate panitumumab study achieved disease control
Outcome
Panitumumab + BSC
(n = 231)
BSC Alone
(n = 232)
Disease control, n (%)
83 (36)
24 (10)
Partial response
19 (8)
0 (0)
Stable disease
64 (28)
Median time to response, wks (min, max)
8 (7, 15) --
Median duration of response, wks (min, max)
17 (4, 40)
Peeters M, et al. AACR Abstract CP-1.

26. Panitumumab vs BSC: Other Outcomes
Panitumumab generally well tolerated
No patients experienced grade 3/4 infusion reactions
Safety Outcome, %
Panitumumab + BSC
(n = 229)
BSC Alone
(n = 234)
Any grade 3/4 adverse event 34 19
Grade 3/4 skin toxicity 14
Dermatitis acneiform 7
Erythema 5
Pruritus 2
Rash 1
Grade 3/4 hypomagnesemia 3
Peeters M, et al. AACR Abstract CP-1.

27. VEGF-Targeted Therapy
VEGF pathway implicated in angiogenesis
Inhibition of VEGF curbs angiogenesis, slows production of new blood vessels necessary for tumor growth
Monoclonal antibody against VEGF
Bevacizumab
Anti-VEGFR TKIs
Sunitinib
Sorafenib

28. Bevacizumab-Irinotecan in Metastatic Colorectal Cancer
IFL Placebo
(n = 411) PD
Patients with untreated metastatic colorectal cancer
(N = 923)
IFL Bevacizumab 5 mg/kg; every 2 weeks
(n = 402)
PD*
IFL: 5-FU, 500 mg/m2; LV, 20 mg/m2; irinotecan, 125 mg/m2; once weekly for 4 weeks, every-6-week cycle
5-FU/LV: 500 mg/m2; LV, 500 mg/m2; once weekly for 6 weeks, every 8-week cycle
5-FU/LV Bevacizumab 5 mg/kg; every 2 weeks
(n = 110)
PD*
Primary endpoint: survival.
*Patients receiving bevacizumab could continue therapy past disease progression in combination with second-line therapy.
Hurwitz H, et al. N Engl J Med. 2004;350:

29. Bevacizumab-Irinotecan in Metastatic Colorectal Cancer (cont’d)
IFL + Placebo
(n = 411)
IFL + Bevacizumab (5 mg/kg, q2w)
(n = 402)
P Value HR
Median survival, mos
15.6
20.3
< .001*
0.66
PFS, mos
6.4
10.6
0.54
ORR, % 35 45
< .01†
Median duration of response, mos
7.1
10.4
.001
0.62 (for relapse)
*By stratified log-rank test.
†By chi2 test.
Hurwitz H, et al. N Engl J Med. 2004;350:

30. The BICC-C Study: Original Design
FOLFIRI Irinotecan 180 mg/m2 Day 1 LV 100 mg/m2 over 2 hours Day 1 5-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1, 2 every 2 weeks (n = 144)
Second randomization (all subjects)
Celecoxib 400 mg twice daily
Patients with previously untreated metastatic colorectal cancer
(N = 430)
mIFL Irinotecan 125 mg/m2 Days 1, 8 LV 20 mg/m2 over 2 hours Days 1, 8 5-FU 500 mg/m2 bolus Days 1, 8 every 3 weeks (n = 141)
Placebo
CapIRI Irinotecan 250 mg/m2 Day 1 Capecitabine 1000 mg/m2 twice daily Days 1-14 every 3 weeks (n = 145)
Primary endpoint: PFS for FOLFIRI vs mIFL.
Fuchs C, et al. ASCO Abstract 3506.

31. The BICC-C Study: Modified Design
Second randomization (all subjects)
FOLFIRI Bevacizumab 5.0 mg/kg; every 2 weeks
(n = 57)
Celecoxib 400 mg twice daily
Patients with previously untreated metastatic colorectal cancer
After May 2004, patients randomized to FOLFIRI or mIFL plus bevacizumab
(N = 117)
mIFL Bevacizumab 7.5 mg/kg; every 3 weeks
(n = 60)
Placebo
CapIRI every 3 weeks
Fuchs C, et al. ASCO Abstract 3506.

32. The BICC-C Study: Results
Longer median PFS with FOLFIRI vs mIFL or CapIRI (prior to addition of bevacizumab)
FOLFIRI vs mIFL: 8 mos vs 6.2 mos; P = .01
FOLFIRI vs CapIRI: 8 mos vs 5.7 mos; P = .01
Significant improvement in OS with FOLFIRI + bevacizumab compared with mIFL + bevacizumab
HR: 2.5 (95% CI: ; P = .01)
Median OS not reached for FOLFIRI + bevacizumab vs mos for mIFL + bevacizumab
No effect with celecoxib
Fuchs C, et al. ASCO Abstract 3506.

33. BICC-C: Safety and Tolerability
More discontinuations in CapIRI group due to toxicity vs FOLFIRI or mIFL groups
17% vs 7% and 12%, respectively
Selected grade 3/4 events (prior to addition of bevacizumab)
Grade 3/4 Adverse Events, %
FOLFIRI (n = 144)
mIFL (n = 141)
CapIRI (n = 145)
Neutropenia 40 39 31
Febrile neutropenia 2 7 5
Diarrhea 13 19 48
Hand-foot syndrome 10
Dehydration 6
Fuchs C, et al. ASCO Abstract 3506.

34. TREE 1 Study Design
mFOLFOX
Oxaliplatin 85 mg/m2 Day 1
LV 350 mg/m2 Day 1
5-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1, 2 every 2 weeks (n = 50)
Patients with inoperable, metastatic colorectal cancer
No prior chemotherapy for metastatic disease
(N = 223)
bFOL
Oxaliplatin 85 mg/m2 Days 1, 15
LV 20 mg/m2 over 2 hours Days 1, 8, 15
5-FU 500 mg/m2 bolus Days 1, 8, 15 every 4 weeks (n = 50)
CapeOx
Oxaliplatin 130 mg/m2 Day 1
Capecitabine 1000 mg/m2 twice daily Days 1-15
every 3 weeks
(n = 50)
Primary endpoint: grade 3/4 toxicity. Secondary endpoints: RR, TTP, TTF.
Hochster HS, et al. ASCO Abstract 3510.

35. TREE 2 Study Design*
mFOLFOX Bevacizumab 5.0 mg/kg every 2 weeks (n = 75)
bFOL Bevacizumab 5.0 mg/kg every 4 weeks (n = 74)
Patients with inoperable, metastatic colorectal cancer
(N = 223)
CapeOx† Bevacizumab 7.5 mg/kg every 3 weeks (n = 74)
*TREE 1 study modified to include bevacizumab.
†Reduced dose of capecitabine used in TREE 2: 850 mg/m2 Days 1-15.
Hochster HS, et al. ASCO Abstract 3510.

36. TREE Study: Efficacy Data
CapeOx
bFOL
mFOLFOX
Overall Response Rate
Median TTP
Median OS 10 20 30 40 50 60 5 10 15 20 25 30 53 27 26 48 43 41 20 19 35 17 17
Patients (%)
Months 22 10 9 8 8 6 5
TREE 1
TREE 2*
TREE 1
TREE 2*
TREE 1
TREE 2*
*With bevacizumab.
Hochster HS, et al. ASCO Abstract 3510.

37. TREE: Summary of Safety and Tolerability
Fewer treatment-related events in bFOL arm vs CapeOx or FOLFOX during first 12 weeks of treatment
Increased hypertension with addition of bevacizumab
Tolerability of CapeOx improved with capecitabine dose reduction in TREE 2
Treatment-Related Events, % (95% CI)
FOLFOX
bFOL
CapeOx
TREE 1
59 (44-73) n = 49
36 (23-51)
n = 50
67 (52-80)
n = 48
TREE 2
59 (47-71) n = 71
51 (39-64) n = 70
56 (43-67) n = 72
Hochster HS, et al. ASCO Abstract 3510.

38. ECOG E3200: Bevacizumab for Previously Treated Metastatic Disease
FOLFOX4 Oxaliplatin 85 mg/m2 Day 1 Leucovorin 200 mg/m2 IV over 2 hrs 5-FU 400 mg/m2 bolus, then 600 mg/m2 over 22-hr continuous infusion Days 1-2 every 2 weeks (n = 290)
Previously treated, bevacizumab-naive patients with metastatic CRC
(N = 822)
Terminated in March 2003 due to inferiority vs other arms
Bevacizumab 10 mg/kg every 2 weeks
(n = 243)
FOLFOX4 + Bevacizumab Oxaliplatin 85 mg/m2 Day 1 Leucovorin 200 mg/m2 IV over 2 hrs 5-FU 400 mg/m2 bolus, then 600 mg/m2 over 22-hr continuous infusion Days 1-2 every 2 weeks Bevacizumab 10 mg/kg every 2 weeks
(n = 289)
Giantonio BJ, et al. ASCO Abstract 2.

39. ECOG E3200: Outcome With Addition of Bevacizumab
Progression-free and overall survival increased with bevacizumab + FOLFOX4
Increased toxicity with bevacizumab +FOLFOX4
3 bowel perforations reported in this group
Efficacy and Tolerability of FOLFOX4 ± Bevacizumab
Outcome
FOLFOX4 + Bevacizumab
FOLFOX4
P Value
Median OS, mos
12.9
10.8
.0018
Median PFS, mos
7.2
4.8
< .0001
Overall response rate, %
21.8
9.2
< .001
Adverse event, %
Grade 3/4 hypertension
5/1
2/< 1
.018
Grade 3/4 bleeding
3/1
< 1/0
.011
Grade 3/4 neuropathy
16/< 1
9/< 1
.016
Grade 3/4 vomiting
9/1
3/< 1
.010
Giantonio BJ, et al. ASCO Abstract 2.

40. Valatinib in Untreated Patients With Metastatic Colorectal Cancer
FOLFOX4/Valatinib
Oxaliplatin 85 mg/m2 Day 1
Leucovorin 200 mg/m2 IV over 2 hrs + 5-FU 400 mg/m2 bolus, followed by
5-FU 600 mg/m2 continuous infusion
over 22 hrs on Days 1-2 every 2 weeks
Valatinib 1250 mg orally once daily
(n = 585)
Patients with previously untreated metastatic CRC
(N = 1168)
FOLFOX4
Leucovorin 200 mg/m2 IV over 2 hrs + 5-FU 400 mg/m2 bolus
5-FU 600 mg/m2 continuous infusion
over 22 hrs on Days 1-2 every 2 weeks
Placebo orally once daily
(n = 583)
PS, performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal
Stratification by PS (0/1 vs 2)
and low vs high LDH
(≤ 1.5 vs > 1.5 x ULN)
Hecht J, et al. ASCO Abstract LBA3.

41. Valatinib in Untreated Patients With Metastatic Colorectal Cancer (cont’d)
Adding valatinib to FOLFOX4 did not improve response
CR + PR = 42% vs 46% with FOLFOX4 alone
Slight improvement in PFS in secondary investigator analysis
Patients with high LDH levels treated with FOLFOX4/valatinib showed improved PFS
HR: 0.67; P = .010 by independent assessment
HR: 0.61; P = .002 by investigator analysis
More patients on valatinib + FOLFOX4 discontinued treatment due to adverse events
Most common grade 3/4 adverse events included hypertension, neutropenia, and diarrhea
Hecht J, et al. ASCO Abstract LBA3.

42. Conclusions EGFR-, VEGF-targeting agents plus chemotherapy
Associated with improved activity, survival in metastatic disease
Nontraditional adverse events (eg, hypertension, delayed wound-healing, rash) with targeted therapy
Ongoing studies investigating
Maintenance therapy with targeted agents between chemotherapy-free intervals
Combinations of several targeted agents