Bevacizumab%20(Bev)%20in%20combination%20with%20XELOX%20or%20FOLFOX-4:%20updated%20efficacy%20results%20from%20XELOX-1%20/%20NO16966,%20a%20randomized%20phase%20III%20trial%20in%20first-line%20metastatic%20colorectal%20cancer

1
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 L1, Clarke S2, Diaz-Rubio E3, Scheithauer
  W4, Figer A5Wong R6, Koski S7, Lichinitser M8,
  Yang T9, Cassidy J10
• 1Memorial Sloan Kettering Cancer Center, New
  York, USA, 2University of Sydney and Sydney
  Cancer Centre, Sydney, Australia, 3Hospital
  Clínico San Carlos, Madrid, Spain, 4Vienna
  University Medical School, Vienna, Austria, 5Tel
  Aviv Sourasky Medical Center, Tel Aviv, Israel,
  6Cancer Care Manitoba, St Boniface General
  Hospital, Winnipeg, MB, Canada, 7Cross Cancer
  Institute, Edmonton, AB, Canada, 8Russian Cancer
  Research Center, Moscow, Russian Federation,
  9Chang-Gung Memorial Hospital, Taipei, Taiwan,
  10Glasgow University, Glasgow, Scotland

2
Introduction

• NO16966 (XELOX-1) started as a multinational,
  2-arm, open-label, randomized phase III
  comparison of XELOX (oxaliplatin 130mg/m2 i.v.
  day 1 capecitabine 1000mg/m2 orally bid days
  1-14, every 3 weeks) vs. FOLFOX-4 (oxaliplatin
  85mg/m2 i.v. day 1 5-FU 400mg/m2 i.v. day 1
  folinic acid 200mg/m2 i.v. day 1)1 (Figure 1).
• After pivotal phase III data for bevacizumab
  became available,2 the protocol was amended to a
  partially blinded randomized, 2 x 2 factorial
  design with two co-primary objectives.
• Previously reported results showed that in terms
  of progression-free survival (PFS), bevacizumab
  is superior to placebo when combined with
  oxaliplatin-based chemotherapy (XELOX /
  FOLFOX-4).3
• Here we present updated overall survival data
  with an additional 1 year of follow-up.

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XELOX-1 / NO16966 study design

• The study was double-blind with regard to
  bevacizumab and placebo administration, but not
  for capecitabine and 5-FU, since these are
  administered orally and intravenously,
  respectively (Figure 1).
• Recruitment occurred in two phases as the
  protocol was amended to include a
  placebo-controlled comparison with bevacizumab.

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Figure 1. XELOX-1 / NO16966 study design
RecruitmentJune 2003 May 2004
RecruitmentFeb 2004 Feb 2005
XELOX placebo n350
XELOX bevacizumab n350
XELOX n317
FOLFOX-4 placebo n351
FOLFOX-4 bevacizumab n349
FOLFOX-4 n317
Protocol amended to 2x2 placebo-controlled design
after bevacizumab phase III data2 became
available (n1400)
Initial 2-arm open-label study (n634)
5
Treatment schedules

• XELOX bevacizumab (or placebo)
• Bev (or placebo) 7.5 mg/kg i.v. over 3090
  min, day 1
• Oxaliplatin 130 mg/m2 i.v. over 2 hrs, day 1
• Capecitabine 1000 mg/m2 orally, twice daily,
  days 114
• Schedule repeated every 21 days
• FOLFOX-4 bevacizumab (or placebo)
• Bev (or placebo) 5 mg/kg i.v. over 3090
  min, day 1
• Oxaliplatin 85 mg/m2 i.v. over 2 hrs, day 1
• Folinic acid 200 mg/m2 i.v. over 2 hrs, days 1,
  2
• Fluorouracil 400 mg/m2 i.v. bolus, days 1, 2
• Fluorouracil 600 mg/m2 i.v. inf over 22 hrs,
  days 1, 2
• Schedule repeated every 14 days

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Main inclusion criteria

• Male or female 18 years old
• ECOG PS 1
• Histologically confirmed adenocarcinoma of colon
  or rectum with metastatic disease
• 1 unidimensionally measurable lesion
• No prior systemic therapy for advanced/MCRC
• No prior treatment with oxaliplatin or
  bevacizumab
• If prior adjuvant therapy patients must not have
  progressed during or within 6 months of
  completion
• No CNS disease, including brain metastases
• No clinically significant cardiovascular disease
• No moderate or severe renal impairment
• No proteinuria 1
• Neutrophils 1.5 x 109/L.

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Primary and secondary objectives

• Primary objectives
• Non-inferiority of XELOX vs. FOLFOX-4 for PFS
• non-inferiority was concluded if the upper limit
  of 97.5 confidence interval (CI) was 1.23.
• Bevacizumab chemotherapy (XELOX and FOLFOX-4)
  is superior to placebo chemotherapy for PFS
• superiority was concluded if p0.025.
• Secondary objectives
• Overall survival.
• Response rate assessed according to RECIST
  criteria. Assessments made by investigators and
  also an independent response committee (IRC).
• Safety evaluated using NCI-CTC (version 3.0).

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Study populations

• ITT (intent-to-treat) all randomized patients.
• EPP (eligible patient population) ITT minus
  major protocol violators and patients not
  receiving at least 1 dose of study drug. Used for
  the XELOX non-inferiority analyses due to health
  authority requirements.
• Safety population all patients receiving at
  least one dose of the respective study drug.

9
Baseline characteristics

• The original 2-arm study recruited 634 patients
  after transition to 2x2 factorial study design,
  an additional 1400 patients were recruited.
• The analysis presented here is based on the 1400
  patients recruited in the 2X2 factorial part of
  the study.
• Baseline patient characteristics were well
  balanced between the groups (Table 1).
• Most patients had 1 or 2 metastatic sites and
  approximately one-quarter of patients had
  received prior adjuvant therapy.

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Table 1. Baseline patient characteristics
FOLFOX-4 placebo (n351) FOLFOX-4 bevacizumab (n349) XELOX placebo (n350) XELOX bevacizumab (n350)
Male/female, 53/47 59/41 59/41 61/39
Median age, years 60 60 61 61
ECOG PS at baseline 0/1, 60/40 57/43 59/41 59/41
Alkaline phosphatase at baseline Abnormal/normal, 42/58 42/58 43/57 45/55
Prior adjuvant chemotherapy No/Yes, 76/24 75/25 74/26 78/22
Cancer type at first diagnosis, Colon and rectal Colon Rectal 7 66 27 8 64 28 9 67 25 9 67 23
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Efficacy

• The co-primary objective was met the addition of
  bevacizumab to oxaliplatin-based chemotherapy
  significantly improved PFS, HR0.83 97.5 CI
  0.720.95, p0.0023 (Figure 2).3,4
• The overall survival analysis presented here
  includes 12 additional months of follow-up.
• Pre-specified on-treatment definition (events
  occuring within 28 days of last dose only)
  showed significant improvement in PFS in
  bevacizumab-treated patients (Figure 3).

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Figure 2. PFS chemotherapy bevacizumab (ITT
population)
XELOX / FOLFOX-4 bevacizumab n699 (513
events) XELOX / FOLFOX-4 placebo n701 (547
events)
1.0 0.8 0.6 0.4 0.2 0
HR0.83 97.5 CI 0.720.95 p0.0023
PFS estimate
9.4
8.0
0 5 10 15 20 25
Months
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Table 2. Secondary endpoints (ITT population)
Placebo FOLFOX-4 or XELOX(n701) Bevacizumab FOLFOX-4or XELOX(n699) P value
Median PFS on treatmenta, months Hazard ratio (97.5 CI) 7.9 10.4 lt0.0001
Time to treatment failureb, months Hazard ratio (97.5 CI) 6.0 6.9 0.0030
Median overall survival, months Hazard ratio (97.5 CI) 19.9 21.3 0.0769
0.63 (0.520.75)
0.84 (0.740.96)
0.89 (0.761.03)
aOn treatment analysis includes only patients who
received treatment as stated in the
protocol. bBased on safety population.

• Response rate (IRC) for XELOX/FOLFOX-4bev and
  XELOX/FOLFOX-4placebo was 38 for each response
  rates (investigator) were 47 and 49,
  respectively.

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Figure 3. Separation after 6 months in
bevacizumab-containing arms between general and
on treatment PFS
XELOX / FOLFOX-4 bevacizumab
XELOX / FOLFOX-4 placebo
1.0 0.8 0.6 0.4 0.2 0
ON TREATMENT HR0.63 (97.5 CI 0.520.75,
plt0.0001)
PFS estimate
GENERAL HR0.83 (97.5 CI 0.720.95,
p0.0023)
0 5 10
15 20
Months
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Figure 4. Overall survival (ITT population)
XELOX / FOLFOX-4 bevacizumab n699 (420
events) XELOX / FOLFOX-4 placebo n701 (455
events)
1.0
HR0.89 (97.5 CI 0.761.03) p0.0769
0.8
Survival estimate
0.6
0.4
0.2
19.9
21.3
0
0
Months
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Treatment exposure

• Duration of treatment was similar in bevacizumab-
  and placebo-containing arms.
• Median treatment duration
• Bevacizumab XELOX 6.1 months (range 015.3)
• Placebo XELOX 5.4 months (range 015.7)
• Bevacizumab FOLFOX-4 6.3 months (014.9)
• Placebo FOLFOX-4 6.0 months (range 015.6).
• Only 29 of bevacizumab recipients and 4450 of
  placebo recipients were treated until disease
  progression.a

aIncludes non-progressive patients stopping
treatment at week 48 (end of primary treatment
phase)
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Table 3. Reasons for treatment discontinuation
Chemotherapy placebo (n701)
Chemotherapy bevacizumab (n699)
582
601
Discontinued treatmenta
334 (56)
221 (38)
Progression eventsa
327
205
Disease progression
7
16
Death
267 (44)
361 (62)
Non-progression eventsa
213
140
Adverse event
1
3
Protocol violation
59
53
Refused treatment
88
74
Other
aDuring primary treatment phase
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Figure 5. Treatment withdrawal over time due to
disease progression
Number of patients
Time from randomization (weeks)
Progression placebo 334 (56)
Progression bevacizumab 221 (38)
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Safety

• A higher proportion of patients discontinued
  therapy because of AEs in the bevacizumab-containi
  ng arms vs. the placebo-containing arms (31 vs.
  21).
• Most treatment discontinuations were due to
  chemotherapy-rather than bevacizumab-related
  events.
• Most common reasons for treatment discontinuation
  were neurotoxicity, GI events, general disorders
  and hematological events.
• Predefined grade 3/4 AEs of interest to
  bevacizumab and chemotherapy are presented in
  Table 3.

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Figure 6. Most frequent grade 3/4 AEs with
chemotherapy placebo or bevacizumab (safety
population)
AEs occuring in gt5 of patients
of patients
VTE venous thromboembolism HFS hand-foot
syndrome
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Table 4. Grade 3/4 events with chemotherapy
placebo or bevacizumab (safety population)
Grade 3/4 event ( of patients) FOLFOX-4 or XELOX placebo (N675) FOLFOX-4 or XELOX bevacizumab (N694)
All Adverse Events 75 80
GI perforations lt1 lt1
Bleeding 1 2
Arterial thromboembolic events 1 2
Hypertension 1 4
Proteinuria lt1
Wound-healing complications lt1 lt1
Discontinuations due to AE 21 31
All-cause 60-day mortality 1.6 2.0
Treatment-related mortality up to 28 days after last dose 1.5 2.0
22
Conclusions

• The addition of bevacizumab to front-line
  oxaliplatin-based chemotherapy significantly
  improves PFS.
• The overall safety profile is in line with
  previous trial experience in colorectal cancer.
• Analysis of on treatment PFS vs. general PFS
  suggests that continuation of bevacizumab until
  disease progression may be necessary to optimize
  the effect of bevacizumab on PFS.
• The observed overall survival difference did not
  reach statistical significance (p0.077).

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Acknowledgement

• Study sponsored by Roche
• Sincere thanks to
• The patients and their families
• The co-investigators
• The research nurses and data managers
• The study management team

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References

• De Gramont A, et al. J Clin Oncol
  2000182938-47.
• Hurwitz H, et al. NEJM 20043502335-42.
• Saltz L, et al. Proc ASCO GI 2007 (Abstr 238).
• Cassidy J, et al. Proc ESMO 2006 (Abstr LBA3).
• Presented at the ASCO Annual Meeting, 1-5 June,
  2007