Transcript Colorectal Update - ASCO 2007

Targeted Therapies in
Metastatic Colorectal
Cancer: An Update
ASCO 2007: Targeted Therapies in
Metastatic Colorectal Cancer: An Update

Bevacizumab is effective in combination with XELOX or FOLFOX-4

Bevacizumab use beyond first progression linked to improvement in
survival outcomes

Cetuximab in combination with FOLFIRI is an effective first-line therapy

Panitumumab is generally well tolerated and has a consistent toxicity
profile across studies
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
FOLFOX-4 = 5-fluorouracil/leucovorin/oxaliplatin
XELOX = capecitabine/oxaliplatin
Bevacizumab is effective in combination
with XELOX or FOLFOX-4
Bevacizumab (Bev) in combination with XELOX
or FOLFOX-4: updated efficacy results from
XELOX-1/NO16966, a randomized phase III
trial in first-line metastatic colorectal cancer
Saltz L, et al. ASCO 2007: Abstract 4028.
Background

Colorectal cancer is the second leading cause of death from cancer
in Canada

Approximately 20,800 new cases of colorectal cancer will be diagnosed
in 2007 alone1

Monoclonal antibodies (MAbs) such as bevacizumab, cetuximab, and
panitumumab in combination with chemotherapy drugs are showing
considerable promise

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody
that inhibits the vascular endothelial growth factor (VEGF), secreted by
tumour cells to bring about new blood vessel formation

Cancer Care Ontario guidelines recommend the addition of bevacizumab
to improve overall survival
•
As first-line therapy in patients with advanced colorectal cancer
receiving 5-fluorouracil (5-FU)–based chemotherapy
•
As second-line therapy to patients who did not receive bevacizumab
as part of their initial treatment2
1. Canadian Cancer Statistics, 2007.
2. Welch, et al. Cancer Care Ontario, 2005.
Background (continued)


The NO16966 trial1 was started as a randomized phase III study
to compare the efficacy of
•
XELOX (capecitabine and oxaliplatin) versus
•
FOLFOX-4 (5-fluorouracil, leucovorin, and oxaliplatin)
The protocol was amended to include bevacizumab in a partially
blinded 2 x 2 factorial design to determine the following objectives:
•
Non-inferiority of XELOX versus FOLFOX-4
•
Superiority of bevacizumab in combination with chemotherapy
(XELOX and FOLFOX-4) versus chemotherapy alone for
progression-free survival (PFS)
.1. Saltz L, et al. ASCO 2007: Abstract 4028.
Study design

The study was a double-blind study with regard to bevacizumab and
placebo administration

Enrolled patient criteria included:
• ECOG PS ≤1
• Number of unidentified measurable lesions ≥1
• No prior systemic therapy for advanced metastatic colorectal cancer
• No prior treatment with oxaliplatin or bevacizumab

Patients who had undergone prior adjuvant therapy should not have
progressed during or within 6 months of completion
Saltz L, et al. ASCO 2007: Abstract 4028.
ECOG = Eastern Cooperative Oncology Group
Study design (continued)
FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin
Saltz L, et al. ASCO 2007: Abstract 4028.
XELOX = capecitabine/oxaliplatin
Study design (continued)
 Patients randomized to XELOX ± bevacizumab or FOLFOX-4 ±
bevacizumab
•
XELOX + bevacizumab or placebo for 21-day cycle
– Bevacizumab (or placebo) 7.5 mg/kg
day 1
– Oxaliplatin 130 mg/m2
day 1
– Capecitabine 1,000 mg/m2 twice daily
days 1–14
•
FOLFOX-4 + bevacizumab or placebo for 14-day cycle
–
–
–
–
Bevacizumab (or placebo) 5 mg/kg
Oxaliplatin 85 mg/m2
Folinic acid 200 mg/m2
Fluorouracil 400 mg/m2 bolus
day 1
day 1
days 1, 2
days 1, 2 — followed
by 600 mg/m2 over 22 h
 Primary endpoint was progression-free survival
 Secondary endpoints were overall survival, response rate assessed
according to RECIST; safety evaluated using NCI CTC v3.0
NCI CTC= National Cancer Institute Common Toxicity Criteria
Saltz L, et al. ASCO 2007: Abstract 4028.
RECIST = response evaluation criteria in solid tumours
Key findings
 Significant prolongation of progression-free survival (PFS) in the
bevacizumab + oxaliplatin–based chemotherapy arm (HR = 0.83
[97.5% CI: 0.072–0.95]; p = 0.0023)
 Trend toward prolonged overall survival (OS)
 Higher proportion of discontinuation of therapy because of adverse
effects (AEs) that occurred in the bevacizumab-containing arms
versus the placebo-containing arms (31% versus 21%)
 Most treatment discontinuations, however, due to chemotherapy
rather than bevacizumab-related events
 Most common reasons for treatment discontinuation: neurotoxicity,
GI events, general disorders, and hematological events
Saltz L, et al. ASCO 2007: Abstract 4028.
Grade 3 or 4 events with chemotherapy ±
bevacizumab
Saltz L, et al. ASCO 2007: Abstract 4028.
Key conclusions

Significant improvement in progression-free survival (PFS) with the
addition of bevacizumab to front-line oxaliplatin-based chemotherapy

Analysis of ‘on treatment’ PFS versus ‘general’ PFS suggests that
continuation of bevacizumab until disease progression may be
necessary to optimize effect of bevacizumab on PFS

Observed overall survival (OS) difference did not reach statistical
significance (p = 0.077)
Saltz L, et al. ASCO 2007: Abstract 4028.
Canadian perspective by Dr. Cripps

Equivalence of XELOX to FOLFOX-4 and FOLFOX-6 in both
first-line and second-line chemotherapy

Infusional lines not needed with XELOX; this is especially relevant
for pockets in Canada where infusional pumps not available

There are changing toxicities with XELOX versus FOLFOX, but
toxicities can be managed easily

Recently completed phase I study1 found response rates of
first-line capecitabine (X), irinotecan (I), and oxaliplatin (O) to
be very high, overall survival 79%, disease control rate 92; five
patients have gone in for surgical resection. XIO well tolerated

Targeted therapies are here to stay

Level 1 evidence suggests targeted therapy such as bevacizumab
can add 4.4 months to progression-free survival

Now we need to confirm the efficacy and safety of XIO with and
without bevacizumab in a phase II trial
FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin
FOLFOX-6 = infusional 5-fluorouracil/leucovorin/oxaliplatin
1. Maroun J, et al. ASCO 2007: Abstract 4086.
XELOX = capecitabine/oxaliplatin
Bevacizumab use beyond first
progression linked to improvement
in survival outcomes
Association between exposure to bevacizumab (BV)
beyond first progression (BBP) and overall survival
(OS) in patients (pts) with metastatic colorectal cancer
(mCRC): results from a large observational study
(BRiTE).
Grothey A, et al. ASCO 2007: Abstract 4036.
.
Background


No data exist regarding
•
Effects of bevacizumab beyond first progression (BBP)
•
Optimal duration of VEGF inhibition, including long-term safety
and efficacy of using BBP
BRiTE is an observational, non-controlled bevacizumab treatment
registry:
•
Initiated in 2004
•
Evaluates safety and efficacy of bevacizumab in combination
with chemotherapy in large, less-selected, community-based
population of patients with previously untreated mCRC
(metastatic colorectal cancer)
BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects and Safety
Grothey A, et al. ASCO 2007: Abstract 4036.
VEGF = vascular endothelial growth factor
Study design


Patients enrolled from 248 study sites in 49 states between February
2004 and June 2005:
•
Group of 1,953 evaluable patients
•
Metastatic or locally advanced and unresectable colorectal cancer
•
No prior therapy for their metastatic disease
•
Patients with poor ECOG PS also included in the study
Investigator decided on
•
Dose, schedule, and duration of bevacizumab
•
Dose, schedule and choice per duration of chemotherapy regimen

Primary endpoint: survival beyond first progression

Secondary endpoints: time to progression, and overall survival or study
termination
Grothey A, et al. ASCO 2007: Abstract 4036.
ECOG PS = Eastern Cooperative Oncology Group performance status
Key findings

In bevacizumab beyond first progression (BBP) subgroup:
•
Longer survival beyond first progression
•
Longer median overall survival

No appreciable difference in bevacizumab-associated safety events
between BBP and No BBP subgroups

No appreciable increase in incidence of bevacizumab-associated
safety events post–first progression observed in BBP subgroup:

•
Arterial thromboembolic events
•
Grade 3 or 4 bleeding events
•
GI perforation
No apparent increase in incidence of bevacizumab-specific adverse
events (AEs) in BBP subgroup
Grothey A, et al. ASCO 2007: Abstract 4036.
Key conclusions

Median overall survival (OS) in BRiTE is 25.1 months, longer than
OS previously reported from phase III trial AVF2107 (median OS
20.3 months), despite unselected population

Substantially longer median OS and survival beyond first
progression in the BBP versus the No BPP subgroups

Similar overall rates of bevacizumab-associated safety events prior
to first progression or after first progression in the BBP subgroup,
compared to patients who received bevacizumab only

First report of improvement in survival outcomes associated with
BBP for patients who started bevacizumab in first-line setting
BBP = bevacizumab beyond first progression
Grothey A, et al. ASCO 2007: Abstract 4036.
BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects andSafety
Cetuximab in combination with FOLFIRI
is an effective first-line therapy
Randomized phase III study of irinotecan and
5-FU/FA with or without cetuximab in the first-line
treatment of patients with metastatic colorectal
cancer (mCRC): the CRYSTAL trial
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
Background

The epidermal growth factor receptor (EGFR) belongs to the human
epidermal growth factor receptor (HER) family of transmembrane
receptors

Aberrant cell signalling, mediated through EGFR, plays a pivotal role
in tumorigenesis and disease progression

Monoclonal antibodies such as cetuximab and panitumumab
prevent the binding of the epidermal growth factor and TGF-alpha
to the EGFR, and bring about inhibition of cell proliferation1

Common side effects of anti-EGFR therapy include skin toxicities
such as acneiform dermatitis, pruritis, erythema, rash, and dry skin
1. McKarney L, et al. New Evidence in Oncology 2006.
TGF = transforming growth factor
Background (continued)

Appearance of skin rash may be useful as a surrogate marker of
EGFR efficacy

Ongoing studies are attempting to elucidate characteristics of target
rashes that may correlate with better anti-EGFR response

CRYSTAL trial initiated to investigate addition of cetuximab to
FOLFIRI as first-line treatment EGFR-expressing metastatic
colorectal cancer1

The correlation of severity of skin toxicity with PFS was a
secondary endpoint
EGFR = epidermal growth factor receptor
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
1. Van Cutsem E, et al. ASCO 2007: Abstract 4000.
TGF = transforming growth factor
Study design

Patients (n = 1,217) enrolled from 32 countries had:
• Histologically confirmed unresectable metastatic colorectal cancer
• EGFR expression in primary tumour or metastasis as detected by IHC
• Tumours ≥1 bi-dimensionally measurable lesion
• No previous chemotherapy for metastatic disease; adjuvant therapy
allowed if stopped minimum 6 months previous (no irinotecan)
• ECOG PS ≤ 2 at study entry

Randomized 1:1 to receive either:
•
Group A: cetuximab plus FOLFIRI
– QW: cetuximab: 400 mg/m2 initial dose, then 250 mg/m2/week
– Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus
400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours, or
•
Group B: FOLFIRI alone
–
Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus
400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours
ECOG = Eastern Cooperative Oncology Group
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
IHC = immunohistochemistry
Study design (continued)

Patient population:
•
Total randomized patients (n = 1,217)
•
Population evaluated for safety (n = 1,202)
•
Intent to treat population (n = 1,198)

Primary endpoint: progression-free survival

Secondary endpoints:
•
Overall survival
•
Overall response rate (ORR)
•
Disease control rate (DCR)
•
QoL (EORTC QLQ C30)
•
Safety
EORTC = European Organisation for Research and Treatment of Cancer
QLQ C30 = Quality of Life Questionnaire
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
QoL = quality of life
Key findings

Progression-free survival (PFS) found to be significantly prolonged
with addition of cetuximab to FOLFIRI
Subgroup analysis of PFS:
•
Pronounced PFS benefit seen in patients with metastases only
to liver
•
More favourable PFS with cetuximab plus FOLFIRI in other
subgroups, except for patients with ECOG PS 2 at baseline
•
Significantly longer median PFS for Group A versus Group B
(8.9 months and 8 months, respectively, stratified log-rank
p-value = 0.0479) (Table 1)
ECOG PS = Eastern Cooperative Oncology Group performance status
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
Progression-free survival
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
Key findings (continued)
•
Significant increase in response rate with cetuximab (46.9%
versus 38.7%, p = 0.0038) (Figure 1)
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
Key findings (continued)
•
Significantly more patients underwent surgery with curative
intent (p = 0.0034) and had successful resection in cetuximab
arm (Figures 2 and 3)
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
Key findings (continued)
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
Safety

Treatment generally well tolerated; neutropenia, diarrhea, and skin
reactions most common grade 3 or 4 adverse events (Table 2)
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
Safety (continued)

More grade 3 skin reactions associated with cetuximab vs. control

Slightly higher incidence of diarrhea

Other adverse events, including neutropenia, comparable in groups

Better PFS outcomes associated with severity of skin reaction seen
in cetuximab-treated patients. Median progression-free survival
(PFS):
•
Grade 3 skin reactions: 11.3 months
•
Grade 2 skin reactions: 9.4 months
•
Grade 0 or 1 skin reactions: 5.4 months
Van Cutsem E, et al. ASCO 2007: Abstract 4000
Key conclusions

Significant increase in response rate and progression-free survival
in the cetuximab plus FOLFIRI arm

Relative risk of progression reduced by approximately 15% in the
cetuximab plus FOLFIRI group

Treatment-related side effects of cetuximab plus FOLFIRI as
expected: moderate occurrence of diarrhea and significantly more
frequent skin reactions compared to FOLFIRI alone
Van Cutsem E, et al. ASCO 2007: Abstract 4000.
FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan
Panitumumab is generally well tolerated
and has a consistent toxicity profile
across studies
Safety of panitumumab, a fully human monoclonal
antibody against the epidermal growth factor
receptor (EGFR), in patients (pts) with metastatic
colorectal cancer (mCRC) across clinical trials
Peeters M, et al. ASCO 2007: Abstract 4138.
Background

Study presented pooled safety data of panitumumab monotherapy
from ten phase I to III clinical trials1

Many studies report clinical activity and tolerability of panitumumab
in EGFR-expressing mCRC patients who had progressed during or
after completion of chemotherapy with fluoropyrimidine-, oxaliplatin-,
and irinotecan-containing regimens

Panitumumab:
•
Recombinant fully human IgG2 MAb
•
Binds specifically to the EGFR
•
Competitively inhibits the binding of ligands to receptor
EGFR= epidermal growth factor receptor
IgG = immunoglobulin G
MAb = monoclonal antibody
1. Peeters M, et al. ASCO 2007: Abstract 4138.
mCRC = metastatic colorectal cancer
Study design

Pooled safety data from ten clinical studies (n = 966) of panitumumab
monotherapy in patients with mCRC

Patients with mCRC and ECOG PS 0-2 included in study (one patient
ECOG PS 3)

Primary endpoints: clinical safety events including
• Incidence of adverse events, including skin-related toxicity and
infusion reactions
• Deaths
• Drug exposure
• Incidence of dose changes
• Immunogenicity of panitumumab

Secondary endpoints: changes in metabolic and laboratory assessments
after panitumumab infusions
ECOG PS = Eastern Cooperative Oncology Group performance status
Peeters M, et al. ASCO 2007: Abstract 4138.
mCRC = metastatic colorectal cancer
Study design (continued)

Panitumumab administered by infusion over 30 to 60 minutes
per protocol; premedication not required. Dosing schedule shown
in Table 1
Peeters M, et al. ASCO 2007: Abstract 4138.
Key findings

Safety results summarized in Tables 2, 3, and 4

Fifteen percent of patients (149) died during the study (including deaths
within 30 days of last dose of panitumumab). Two deaths considered to
be treatment related:
• Pulmonary edema in patient with history of hypercoagulation, deep
vein thrombosis, peripheral vascular disease, and diabetes mellitus
• Myocardial infarction and cerebrovascular accident observed in patient
with history of anemia, diabetes mellitus, deep vein thrombosis,
hyperlipidemia, hypertension, and supraventricular tachycardia

Antibodies to panitumumab: patients who were predose negative and
had persistent postdose positive results:
• ELISA found 2/778 patients (0.3%) tested positive for
anti-panitumumab antibodies
• Biacore found 2/638 patients (0.4%) tested positive for
anti-panitumumab antibodies
• Bioassay determined 6/638 patients (1%) had neutralizing antibodies
to panitumumab
Peeters M, et al. ASCO 2007: Abstract 4138.
Incidence of skin-related toxicity
Peeters M, et al. ASCO 2007: Abstract 4138.
Adverse events excluding skin-related toxicity
Peeters M, et al. ASCO 2007: Abstract 4138.
Infusion reactions reported per investigator
Peeters M, et al. ASCO 2007: Abstract 4138.
Key conclusions

Panitumumab generally well tolerated with consistent toxicity profile
across studies

Common toxicities included fatigue, gastrointestinal side effects,
and skin-related (majority were grade 1 or 2)

Grade 3 or 4 infusion reactions rare (0.4% of patients); no
premedication required

Treatment-related adverse events of grade 3 or 4 reported in
20% patients

Four percent of patients permanently discontinued panitumumab
or withdrew from study due to treatment-related adverse events

Anti-panitumumab antibody formation postdose was detected in
<1% of patients by ELISA and Biacore

Incidence of skin-related adverse events in Figure 1
Peeters M, et al. ASCO 2007: Abstract 4138.
Figure 1 : Any skin-related adverse events
Peeters M, et al. ASCO 2007: Abstract 4138.