Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy

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
• Associate Professor, Hematology/Oncology
• 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.
200656106-130.2. Kamangar F, et al. J Clin
Oncol. 2006 242137-2150.
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. 20003421960-1968.
Vogelstein B, et al. N Engl J Med.
1988319525-532.
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, 1998565-87.
Vogelstein B, et al. N Engl J Med.
1988319525-532. Fearon ER, et al. Cell.
199061759-767.
6
Screening and Cancer Prevention

• Screening with colonoscopy may detect
  precancerous polyps and other early-stage
  disease1
• 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 adenomas2,3
• Despite these techniques, 25 of patients
  present with metastatic disease4
• Nearly one half of patients with colorectal
  cancer require systemic therapy

1. Regula J, et al. N Engl J Med.
20063551863-1872. 2. Baron JA, et al. N Engl J
Med. 2003348891-899. 3. Bertagnolli MM, et al.
N Engl J Med. 2006355873-874.
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-FUbased 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
Grothey A, et al. J Clin Oncol.
2005239441-9442.
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. 2005239441-9442.
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.
199816301-308. Saltz LB, et al. N Engl J Med
2000343905-914. de Gramont A, et al. J Clin
Oncol. 2000182938-2947. Goldberg RM, et al. J
Clin Oncol. 2002204591-4596. Tournigand C, et
al. J Clin Oncol. 200422229-237.
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. 200510250-261 Mayer A,
et al. Cancer. 1993712454-2560.
13
EGFR Inhibitors in Colorectal Cancer (contd)

• To date, few promising results with EGFR-targeted
  TKIs in colorectal cancer setting
• Phase II gefitinib study in 110 patients with
  refractory disease1
• 2 doses studied, only 1 response noted in
  higher-dose (500 mg) group
• No objective responses noted in study of
  erlotinib in second-line setting2
• To date, monoclonal antibodies have exhibited
  better activity in metastatic disease

1. Rothenberg ML, et al. J Clin Oncol.
2005239265-9274.2. Townsely CA, et al. Br J
Cancer. 2006941136-1143.
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)
PD
PD, progressive disease. Primary endpoint
response.
Cunningham D, et al. N Engl J Med.
2004351337-345.
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 (17.5-29.1) 10.8 (5.7-18.1) .0074
Disease control, (95 CI) 55.5 (48.6-62.2) 32.4 (23.9-42.0) .0001
Median TTP, mos 4.1 1.5 lt .0001
Median survival, mos (95 CI) 8.6 (7.6-9.6) 6.9 (5.6-9.1) .48
Disease control complete and partial responses
stable disease.
Cunningham D, et al. N Engl J Med.
2004351337-345.
16
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 2005. 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/IRI/BEV
CET/BEV
CET/IRI/BEV
CET/BEV
CET
CET/IRI
CET
CET/IRI
80
P .03
60
5.6
P lt .01
Partial Response ()
1.5
37
P .05
40
7.9
23
P lt .01
23
4.0
20
11
0
2
4
6
8
10
12
0
Historical controls.
Time to Tumor Progression (Mos)
Saltz L, et al. ASCO 2005. Abstract 3508.
18
BOND and BOND-2 Safety

• BOND overall incidence of adverse events higher
  in cetuximab-irinotecan arm 65 vs 44 P lt .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.
2004351337-345.Saltz L, et al. ASCO 2005.
Abstract 3508.
19
CALGB 80203 Study Design
FOLFOXOxaliplatin 85 mg/m2 Days 1, 8LV 20 mg/m2
over 2 hours Days 1, 85-FU 500 mg/m2 bolus, Days
1, 8every 3 weeks
Patients with untreated metastatic colorectal
cancer (N 238)
FOLFIRIIrinotecan 180 mg/m2 Day 1LV 400 mg/m2
over 2 hours Day 15-FU 400 mg/m2 bolus, then
2400 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 2006. 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
Response, (P .029) Chemotherapy Cetuximab Chemotherapy Alone
ORR (CR PR) 52 38
Venook A, et al. ASCO 2006. 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 mFOLFOX6orFOLFIRI
Bevacizumab 5 mg/kg IV every 2 weeks
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once
weeklyBevacizumab 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 3520. Hecht J.
ASCO GI 2006. 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 2006. Abstract CP-1.
24
Panitumumab vs BSC Main Findings

• PFS significantly better for panitumumab-treated
  patients
• HR 0.54 (95 CI 0.44-0.66 P lt .000000001)

50
Panitumumab BSC
40
BSC
30
Progression Free ()
20
10
Median follow-up 19 weeks.
1
1
1
4
30
49
35
14
26
9
18
5
10
4
0
Wk 8
Wk 12
Wk 16
Wk 24
Wk 32
Wk 40
Wk 48
Peeters M, et al. AACR 2006. Abstract CP-1.
25
Panitumumab vs BSC Main Findings (contd)

• 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) 24 (10)
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 2006. 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 0
Dermatitis acneiform 7 0
Erythema 5 0
Pruritus 2 0
Rash 1 0
Grade 3/4 hypomagnesemia 3 0
Peeters M, et al. AACR 2006. 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
IFLPlacebo (n 411)
PD
Patients with untreated metastatic colorectal
cancer (N 923)
IFLBevacizumab 5 mg/kg every 2 weeks (n 402)
PD
5-FU/LVBevacizumab 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.
20043502335-2342.
29
Bevacizumab-Irinotecan in Metastatic Colorectal
Cancer (contd)
IFL Placebo (n 411) IFL Bevacizumab (5 mg/kg, q2w) (n 402) P Value HR
Median survival, mos 15.6 20.3 lt .001 0.66
PFS, mos 6.4 10.6 lt .001 0.54
ORR, 35 45 lt .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.
20043502335-2342.
30
The BICC-C Study Original Design
FOLFIRI Irinotecan 180 mg/m2 Day 1LV 100 mg/m2
over 2 hours Day 15-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)
mIFLIrinotecan 125 mg/m2 Days 1, 8LV 20 mg/m2
over 2 hours Days 1, 85-FU 500 mg/m2 bolus Days
1, 8every 3 weeks(n 141)
Placebo
CapIRIIrinotecan 250 mg/m2 Day 1Capecitabine
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 2006. Abstract 3506.
31
The BICC-C Study Modified Design
Second randomization (all subjects)
FOLFIRI Bevacizumab 5.0 mg/kgevery 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)
mIFLBevacizumab 7.5 mg/kg every 3 weeks (n
60)
Placebo
CapIRIevery 3 weeks
Fuchs C, et al. ASCO 2006. 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 1.3-5.0 P .01)
• Median OS not reached for FOLFIRI bevacizumab
  vs 18.8 mos for mIFL bevacizumab
• No effect with celecoxib

Fuchs C, et al. ASCO 2006. 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 0 0 10
Dehydration 6 7 19
Fuchs C, et al. ASCO 2006. 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 2006. Abstract 3510.
35
TREE 2 Study Design
mFOLFOX Bevacizumab 5.0 mg/kg every 2 weeks(n
75)
bFOL Bevacizumab 5.0 mg/kgevery 4 weeks(n 74)
Patients with inoperable, metastatic colorectal
cancer (N 223)
CapeOxBevacizumab 7.5 mg/kgevery 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 2006. Abstract 3510.
36
TREE Study Efficacy Data
Overall Response Rate
Median TTP
Median OS
53
27
26
48
43
41
20
19
17
17
35
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 2006. 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 2006. Abstract 3510.
38
ECOG E3200 Bevacizumab for Previously Treated
Metastatic Disease
FOLFOX4 Oxaliplatin 85 mg/m2 Day 1Leucovorin
200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus,
then 600 mg/m2over 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
1Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400
mg/m2 bolus, then 600 mg/m2over 22-hr continuous
infusion Days 1-2 every 2 weeks Bevacizumab 10
mg/kg every 2 weeks (n 289)
Giantonio BJ, et al. ASCO 2005. 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 Efficacy and Tolerability of FOLFOX4 Bevacizumab Efficacy and Tolerability of FOLFOX4 Bevacizumab 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 lt .0001
Overall response rate, 21.8 9.2 lt .001
Adverse event, FOLFOX4 Bevacizumab FOLFOX4 P Value
Grade 3/4 hypertension 5/1 2/lt 1 .018
Grade 3/4 bleeding 3/1 lt 1/0 .011
Grade 3/4 neuropathy 16/lt 1 9/lt 1 .016
Grade 3/4 vomiting 9/1 3/lt 1 .010
Giantonio BJ, et al. ASCO 2005. 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)
Stratification by PS (0/1 vs 2) and low vs high
LDH ( 1.5 vs gt 1.5 x ULN)
Hecht J, et al. ASCO 2005. Abstract LBA3.
41
Valatinib in Untreated Patients With Metastatic
Colorectal Cancer (contd)

• 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 2005. 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