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Annals of Oncology
Table: 570P
up to the point of subsequent therapy and a value of 1 from then on; (4)
censoring patients at the time of subsequent anti-EGFR use and adjusting the
informative censoring with the inverse probability-of-censoring weighted (IPCW)
analysis d-f .
Results: Table.
Conclusions: Patients receiving chemotherapy alone crossed over earlier and more
frequently to post-protocol anti-EGFR treatment versus those receiving combination
therapy. All analyses produced results indicating that the lack of a statistically
significant OS benefit estimate may have been due to selective crossover bias. The
results also indicate that IPCW method may be particularly suited for detecting OS
benefits that otherwise would not be detected with an ITT approach that ignores
selective crossover bias.
Disclosure: J. Douillard: AMGEN: Participation in Advisory Boards, speaker in
Symposia compensated MERCK:Participation in Advisory Boards, speaker in
Symposia compensated, Research support ROCHE: Participation in Advisory Boards,
speaker in Symposia compensatedM. Peeters: Consultant/advisory role for Amgen
and also received honoraria and research funding. A. Rong: Employee of Amgen and
holds Amgen stock. S. Siena: Advisory role for Amgen, AstraZeneca, Merck Serono,
Roche, Celgene. S. Braun: Employee of Amgen and holds Amgen stock. R. Sidhu:
Employee of Amgen and holds Amgen stock. T. Price: Consultant/advisory role for
Amgen and received honoraria.
571P BEVACIZUMAB (BEV) + CHEMOTHERAPY (CT) BEYOND FIRST
PROGRESSION IN PATIENTS (PTS) WITH METASTATIC
COLORECTAL CANCER (MCRC) PREVIOUSLY TREATED WITH
FIRST-LINE BEV + CT (ML18147): EFFICACY AND SAFETY
ANALYSES BY OXALIPLATIN VS IRINOTECAN-BASED CT
P. Österlund 1 , V. Alonso-Orduna 2 , C. Schlichting 3 , T. André 4 , J. Sastre 5 ,
R. Greil 6 , S. Kubicka 7 , I. Reyes-Rivera 8 , B. McCall 9 , E.J.D. Van Cutsem 10
1 Medical Oncology, Helsinki University Central Hospital, Helsinki, FINLAND,
2 Servicio De Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza,
SPAIN, 3 I. Chirurgische Klinik, Diakoniekrankenhaus Rotenburg GmbH,
Rotenburg, GERMANY, 4 Medical Oncology, Hopital Saint-Antoine and Université
Pierre et Marie Curie, Paris, FRANCE, 5 Medical Oncology, Servicio de Oncología
Médica HC, Madrid, SPAIN, 6 Oncology Centre, III Medizinische Universitätsklinik
Salzburg, Salzburg, AUSTRIA, 7 Internal Medicine, Cancer Center Reutlingen,
Reutlingen, GERMANY, 8 Statistics, Genentech Inc., South San Francisco, CA,
UNITED STATES OF AMERICA, 9 Product Development, Oncology, Genentech,
Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 10 Digestive
Oncology, University Hospital Gasthuisberg, Leuven, BELGIUM
Background: ML18147 is the first randomised study to show that continuing BEV +
standard CT as second-line (2L) treatment significantly improves overall survival
(OS) and progression-free survival (PFS) in pts with mCRC who progressed after
receiving a standard first-line (1L) BEV-containing regimen. Here we evaluate
outcome in the 2L setting using, as a stratification factor, 1L oxaliplatin vs
irinotecan-based CT.
PRIME 181
Pmab +
FOLFOX4 FOLFOX4
Methods: Pts with unresectable, histologically confirmed mCRC who progressed
within 3 months of discontinuing 1L BEV were randomised to 2L
fluoropyrimidine-based CT ± BEV (2.5 mg/kg/wk equivalent). Choice of 2L
oxaliplatin or irinotecan was dependent on the 1L regimen (crossover). OS, PFS,
overall response rate (ORR) and adverse events (AEs) were analysed in the 2L setting
using the 1L oxaliplatin or irinotecan-based CT as a stratification factor.
Results: 820 pts were randomised from Feb 2006 to Jun 2010. Of these, 343 received
1L oxaliplatin-based CT and 476 received 1L irinotecan-based CT, after which they
crossed over to receive either oxaliplatin or irinotecan-based CT in 2L. BEV + CT
beyond progression prolonged OS and PFS, regardless of whether oxaliplatin or
irinotecan-based CT was used in 1L (Table). ORR was low in CT and BEV +
CT-treated pts in both groups. AEs associated with BEV were generally similar in pts
treated with either oxaliplatin or irinotecan-based CT.
Outcome in 2L
Pmab +
FOLFIRI FOLFIRI
Number of patients
ITT analysis for OS
n = 325 n = 331 n = 303 n = 294
Median OS, months
(95% CI)
23.9 (20.3– 27.7) 19.7 (17.6–22.7) 14.5 (13.0–16.1) 12.5 (11.2–14.2)
HR (95% CI)
Post-protocol anti-EGFR mAb therapy
0.88 (0.73–1.06) 0.92 (0.78–1.10)
Incidence, (%) 13 25 12 34
Median time to use,
months
21.5 15.6 12.4 7.9
OS sensitivity analyses on influence of post-protocol anti-EGFR mAb therapy
Branson-Whitehead,
0.84 (0.68-1.05) 0.90 (0.71, 1.14)
2002 a
Robins and Tsiatis,
1992 b
Allison, 1995 c
IPCW d-f
0.83 (0.66-1.04) 0.89 (0.71, 1.13)
0.68 (0.55-0.83) 1.03 (0.87, 1.23)
0.74 (0.56-0.97) 0.71 (0.53, 0.94)
a Branson and Whitehead, 2002; b Robins and Tsiatis, 1992; c Allison, 1995;
d Rimawi & Hilsenbeck, 2012; e Colleoni et al, 2011; f Robins & Finkelstein, 2000. Abbreviation: CI = confidence interval
1L oxaliplatin-based CT 1L irinotecan-based CT
CT (n =
174)
BEV + CT (n =
169)
CT (n =
236)
BEV +
CT
(n = 240)
Median OS, months 10.0 12.0 9.3 10.9
p-value 0.0524 0.0454
HR (95% CI) 0.79 (0.62–1.00) 0.82 (0.67–1.00)
Median PFS, months 4.2 6.2 3.8 5.4
p-value 0.0005 1%
of pts, %
0.2414 0.7145
Any 52 66 60 61
Hypertension 0 1 2 2
Bleeding/haemorrhage