Intermittent chemotherapy plus either intermittent or continuous cetuximab for
first-line treatment of patients with KRAS wild-type advanced colorectal cancer
(COIN-B): a randomised phase 2 trial.
Author(s): Wasan H(1), Meade AM(2), Adams R(3), Wilson R(4), Pugh C(5), Fisher D(5), Sydes
B(5), Madi A(5), Sizer B(6), Lowdell C(1), Middleton G(7), Butler R(8), Kaplan
R(5), Maughan T(9); COIN-B investigators.
Collaborators: Benstead K, Sizer B, Middleton G, Lowdell C, Wasan H, Wadsley J,
Gaya A, Cleator S, Wagstaff J, Hickish T, McAdam K, Weaver A, Osborne R, Gaya A,
Reed N, De Winton E, Myint S, Marshall E, Adab F, Ford H, Papamichael D, Hickish
T, Moss A, Farrugia D, Bradley C, Nicoll J, Lofts F, Hartley A, Bale C.
Affiliation(s): Author information:
(1)Imperial College Healthcare NHS Trust, London, UK.
(2)MRC Clinical Trials Unit at UCL, London, UK. Electronic address:
a.meade@ucl.ac.uk.
(3)Cardiff University, Cardiff, UK.
(4)Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast,
UK.
(5)MRC Clinical Trials Unit at UCL, London, UK.
(6)Essex County Hospital, Colchester, UK.
(7)University of Birmingham, Birmingham, UK.
(8)University Hospital of Wales, Cardiff, UK.
(9)Cancer Research UK-MRC Gray Institute for Radiation Oncology and Biology,
University of Oxford, Oxford, UK.
Publication date & source: 2014, Lancet Oncol. , 15(6):631-9
BACKGROUND: Advanced colorectal cancer is treated with a combination of cytotoxic
drugs and targeted treatments. However, how best to minimise the time spent
taking cytotoxic drugs and whether molecular selection can refine this further is
unknown. The primary aim of this study was to establish how cetuximab might be
safely and effectively added to intermittent chemotherapy.
METHODS: COIN-B was an open-label, multicentre, randomised, exploratory phase 2
trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with
advanced colorectal cancer who had received no previous chemotherapy for
metastases. Randomisation was done centrally (by telephone) by the Medical
Research Council Clinical Trials Unit using minimisation with a random element.
Treatment allocation was not masked. Patients were assigned (1:1) to intermittent
chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus
continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin
followed by bolus and infused fluorouracil). Patients in both groups received
FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption
(those taking intermittent cetuximab) or planned maintenance by continuing on
weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus
cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption
or maintenance cetuximab, respectively. The primary outcome was failure-free
survival at 10 months. The primary analysis population consisted of patients who
completed 12 weeks of treatment without progression, death, or leaving the trial.
We tested BRAF and NRAS status retrospectively. The trial was registered,
ISRCTN38375681.
FINDINGS: We registered 401 patients, 226 of whom were enrolled. Results for 169
with KRAS wild-type are reported here, 78 (46%) assigned to intermittent
cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to
intermittent cetuximab and 66 of those assigned to continuous cetuximab were
included in the primary analysis. 10-month failure-free survival was 50% (lower
bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI
41) in the continuous group; median failure-free survival was 12.2 months (95% CI
8.8-15.6) and 14.3 months (10.7-20.4), respectively. The most common grade 3-4
adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92
patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]),
and lethargy (20 [26%] vs 19 [21%]).
INTERPRETATION: Cetuximab was safely incorporated in two first-line intermittent
chemotherapy strategies. Maintenance of biological monotherapy, with less
cytotoxic chemotherapy within the first 6 months, in molecularly selected
patients is promising and should be validated in phase 3 trials.
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